250 results on '"Golenbock DT"'
Search Results
2. TLR2 Mediates Recognition of Live Staphylococcus epidermidis and Clearance of Bacteremia
- Author
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Ratner, AJ, Strunk, T, Coombs, MRP, Currie, AJ, Richmond, P, Golenbock, DT, Stoler-Barak, L, Gallington, LC, Otto, M, Burgner, D, Levy, O, Ratner, AJ, Strunk, T, Coombs, MRP, Currie, AJ, Richmond, P, Golenbock, DT, Stoler-Barak, L, Gallington, LC, Otto, M, Burgner, D, and Levy, O
- Abstract
BACKGROUND: Staphylococcus epidermidis (SE) is a nosocomial pathogen that causes catheter-associated bacteremia in the immunocompromised, including those at the extremes of age, motivating study of host clearance mechanisms. SE-derived soluble components engage TLR2; but additional signaling pathways have also been implicated, and TLR2 can play complex, at times detrimental, roles in host defense against other Staphylococcal spp. The role of TLR2 in responses of primary blood leukocytes to live SE and in clearance of SE bacteremia, the most common clinical manifestation of SE infection, is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We studied TLR2-mediated recognition of live clinical SE strain 1457 employing TLR2-transfected cells, neutralizing anti-TLR antibodies and TLR2-deficient mice. TLR2 mediated SE-induced cytokine production in human embryonic kidney cells, human whole blood and murine primary macrophages, in part via recognition of a soluble TLR2 agonist. After i.v. challenge with SE, early (1 h) cytokine/chemokine production and subsequent clearance of bacteremia (24-48 h) were markedly impaired in TLR2-deficient mice. CONCLUSIONS/SIGNIFICANCE: TLR2 mediates recognition of live SE and clearance of SE bacteremia in vivo.
- Published
- 2010
3. Biological activities of Bacteroides forsythus lipoproteins and their possible pathological roles in periodontal disease
- Author
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Hasebe, A., Yoshimura, A., Into, T., Kataoka, H., Tanaka, S., Arakawa, S., Ishikura, H., Golenbock, DT, Sugaya, T., Tsuchida, N., Kawanami, M., Hara, Y., 1000050145265, Shibata, K., Hasebe, A., Yoshimura, A., Into, T., Kataoka, H., Tanaka, S., Arakawa, S., Ishikura, H., Golenbock, DT, Sugaya, T., Tsuchida, N., Kawanami, M., Hara, Y., 1000050145265, and Shibata, K.
- Abstract
Bacteroides forsythus is a gram-negative, anaerobic, fusiform bacterium and is considered to be an etiological agent in periodontal disease. A lipoprotein fraction prepared from B. forsythus cells by Triton X-114 phase separation (BfLP) activated human gingival fibroblasts and a human monocytic cell line, THP-1, to induce interleukin-6 production and tumor necrosis factor alpha production. BfLP was found to be capable of inducing nuclear factor-kappaB translocation in human gingival fibroblasts and THP-1 cells. By using Chinese hamster ovary K1 cells transfected with Toll-like receptor genes together with a nuclear factor-kappaB-dependent CD25 reporter plasmid, it was found that signaling by BfLP was mediated by Toll-like receptor 2 but not by CD14 or Toll-like receptor 4. BfLP induced apoptotic cell death in human gingival fibroblasts, KB cells (an oral epithelial cell line), HL-60 cells (a human myeloid leukemia cell line), and THP-1 cells but not in MOLT4 cells (a T-cell leukemia cell line). Caspase-8, an initiator caspase in apoptosis, was found to be activated in these cells in response to BfLP stimulation. Thus, this study suggested that BfLP plays some etiological roles in oral infections, especially periodontal disease, by induction of cell activation or apoptosis.
- Published
- 2004
4. Hepatitis C Virus Structural Proteins and Activation of Toll-like Receptor 2 and 4
- Author
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Hoffmann, M, primary, Henneke, P, additional, Barth, H, additional, Gissler, B, additional, Paranhos-Baccalà, G, additional, Golenbock, DT, additional, Blum, HE, additional, and Baumert, TF, additional
- Published
- 2005
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5. Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.
- Author
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Ramalho T, Assis PA, Ojelabi O, Tan L, Carvalho B, Gardinassi L, Campos O, Lorenzi PL, Fitzgerald KA, Haynes C, Golenbock DT, and Gazzinelli RT
- Subjects
- Humans, Monocytes, DNA, Mitochondrial metabolism, B7-H1 Antigen genetics, Mitochondria metabolism, Dendritic Cells, Plasmodium genetics, Plasmodium metabolism, Malaria metabolism, Succinates
- Abstract
Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)
- Published
- 2024
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6. The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection.
- Author
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Pereira M, Ramalho T, Andrade WA, Durso DF, Souza MC, Fitzgerald KA, Golenbock DT, Silverman N, and Gazzinelli RT
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- Animals, Mice, Dendritic Cells, Interferon Regulatory Factors genetics, Interleukin-12, Interleukin-1 Receptor-Associated Kinases, Toxoplasmosis
- Abstract
Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2
-/- mice are only slightly susceptible to T. gondii infection, similar to Irak1-/- mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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7. Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation.
- Author
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de Carvalho Ribeiro M, Iracheta-Vellve A, Babuta M, Calenda CD, Copeland C, Zhuang Y, Lowe PP, Hawryluk D, Catalano D, Cho Y, Barton B, Dasarathy S, McClain C, McCullough AJ, Mitchell MC, Nagy LE, Radaeva S, Lien E, Golenbock DT, and Szabo G
- Subjects
- Animals, Mice, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Inflammation, Ethanol adverse effects, Caspase 1 metabolism, Interleukin-1beta metabolism, CARD Signaling Adaptor Proteins metabolism, Hepatitis etiology, Hepatitis, Alcoholic etiology
- Abstract
Background Aims: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood., Approach Results: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced-ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1β release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1β release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1β production, and steatohepatitis in a murine model of AH., Conclusions: Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH., (Copyright © 2023 American Association for the Study of Liver Diseases.)
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- 2023
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8. Malaria Resilience in South America: Epidemiology, Vector Biology, and Immunology Insights from the Amazonian International Center of Excellence in Malaria Research Network in Peru and Brazil.
- Author
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Torres K, Ferreira MU, Castro MC, Escalante AA, Conn JE, Villasis E, da Silva Araujo M, Almeida G, Rodrigues PT, Corder RM, Fernandes ARJ, Calil PR, Ladeia WA, Garcia-Castillo SS, Gomez J, do Valle Antonelli LR, Gazzinelli RT, Golenbock DT, Llanos-Cuentas A, Gamboa D, and Vinetz JM
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- Animals, Biology, Brazil epidemiology, Humans, Mosquito Vectors physiology, Peru epidemiology, Anopheles physiology, Malaria epidemiology, Malaria prevention & control
- Abstract
The 1990s saw the rapid reemergence of malaria in Amazonia, where it remains an important public health priority in South America. The Amazonian International Center of Excellence in Malaria Research (ICEMR) was designed to take a multidisciplinary approach toward identifying novel malaria control and elimination strategies. Based on geographically and epidemiologically distinct sites in the Northeastern Peruvian and Western Brazilian Amazon regions, synergistic projects integrate malaria epidemiology, vector biology, and immunology. The Amazonian ICEMR's overarching goal is to understand how human behavior and other sociodemographic features of human reservoirs of transmission-predominantly asymptomatically parasitemic people-interact with the major Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, and with human immune responses to maintain malaria resilience and continued endemicity in a hypoendemic setting. Here, we will review Amazonian ICEMR's achievements on the synergies among malaria epidemiology, Plasmodium-vector interactions, and immune response, and how those provide a roadmap for further research, and, most importantly, point toward how to achieve malaria control and elimination in the Americas.
- Published
- 2022
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9. The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways.
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Pereira M, Durso DF, Bryant CE, Kurt-Jones EA, Silverman N, Golenbock DT, and Gazzinelli RT
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- Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Vesicular Transport metabolism, Humans, Signal Transduction physiology, Toll-Like Receptor 3 metabolism, Toll-Like Receptor 4 metabolism, Interleukin-1 Receptor-Associated Kinases metabolism, Myeloid Differentiation Factor 88 metabolism
- Abstract
Interleukin-1 receptor-associated kinases (IRAKs) -4, -2, and -1 are involved in transducing signals from Toll-like receptors (TLRs) via the adaptor myeloid differentiation primary-response protein 88 (MYD88). How MYD88/IRAK4/2/1 complexes are formed, their redundancies, and potential non-enzymatic roles are subjects of debate. Here, we examine the hierarchical requirements for IRAK proteins in the context of TLR4 activation and confirmed that the kinase activity of IRAK4 is essential for MYD88 signaling. Surprisingly, the IRAK4 scaffold is required for activation of the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) by both MYD88 and TIR domain-containing adaptor protein inducing IFN-β (TRIF), a unique adaptation in the TLR4 response. IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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10. Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum.
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Crabtree JN, Caffrey DR, de Souza Silva L, Kurt-Jones EA, Dobbs K, Dent A, Fitzgerald KA, and Golenbock DT
- Subjects
- Chromatin, Humans, Interleukin-6 genetics, Plasmodium falciparum, Tumor Necrosis Factor-alpha metabolism, Lymphocytes immunology, Malaria, Falciparum immunology, Monocytes immunology
- Abstract
Plasmodium falciparum (P. falciparum) induces trained innate immune responses in vitro, where initial stimulation of adherent PBMCs with P. falciparum-infected RBCs (iRBCs) results in hyperresponsiveness to subsequent ligation of TLR2. This response correlates with the presence of T and B lymphocytes in adherent PBMCs, suggesting that innate immune training is partially due to adaptive immunity. We found that T cell-depleted PBMCs and purified monocytes alone did not elicit hyperproduction of IL-6 and TNF-α under training conditions. Analysis of P. falciparum-trained PBMCs showed that DCs did not develop under control conditions, and IL-6 and TNF-α were primarily produced by monocytes and DCs. Transwell experiments isolating purified monocytes from either PBMCs or purified CD4+ T cells, but allowing diffusion of secreted proteins, enabled monocytes trained with iRBCs to hyperproduce IL-6 and TNF-α after TLR restimulation. Purified monocytes stimulated with IFN-γ hyperproduced IL-6 and TNF-α, whereas blockade of IFN-γ in P. falciparum-trained PBMCs inhibited trained responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from patients with malaria showed persistently open chromatin at genes that appeared to be trained in vitro. Together, these findings indicate that the trained immune response of monocytes to P. falciparum is not completely cell intrinsic but depends on soluble signals from lymphocytes.
- Published
- 2022
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11. Asymptomatic Plasmodium vivax malaria in the Brazilian Amazon: Submicroscopic parasitemic blood infects Nyssorhynchus darlingi.
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Almeida GG, Costa PAC, Araujo MDS, Gomes GR, Carvalho AF, Figueiredo MM, Pereira DB, Tada MS, Medeiros JF, Soares IDS, Carvalho LH, Kano FS, Castro MC, Vinetz JM, Golenbock DT, Antonelli LRDV, and Gazzinelli RT
- Subjects
- Animals, Anopheles physiology, Asymptomatic Infections epidemiology, Blood parasitology, Brazil epidemiology, Cohort Studies, Cross-Sectional Studies, Female, Humans, Malaria, Vivax epidemiology, Malaria, Vivax parasitology, Male, Middle Aged, Plasmodium vivax genetics, Seasons, Anopheles parasitology, Malaria, Vivax transmission, Plasmodium vivax physiology
- Abstract
Individuals with asymptomatic infection due to Plasmodium vivax are posited to be important reservoirs of malaria transmission in endemic regions. Here we studied a cohort of P. vivax malaria patients in a suburban area in the Brazilian Amazon. Overall 1,120 individuals were screened for P. vivax infection and 108 (9.6%) had parasitemia detected by qPCR but not by microscopy. Asymptomatic individuals had higher levels of antibodies against P. vivax and similar hematological and biochemical parameters compared to uninfected controls. Blood from asymptomatic individuals with very low parasitemia transmitted P. vivax to the main local vector, Nyssorhynchus darlingi. Lower mosquito infectivity rates were observed when blood from asymptomatic individuals was used in the membrane feeding assay. While blood from symptomatic patients infected 43.4% (199/458) of the mosquitoes, blood from asymptomatic infected 2.5% (43/1,719). However, several asymptomatic individuals maintained parasitemia for several weeks indicating their potential role as an infectious reservoir. These results suggest that asymptomatic individuals are an important source of malaria parasites and Science and Technology for Vaccines granted by Conselho Nacional de may contribute to the transmission of P. vivax in low-endemicity areas of malaria., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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12. Clostridioides difficile Toxin A Remodels Membranes and Mediates DNA Entry Into Cells to Activate Toll-Like Receptor 9 Signaling.
- Author
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Chen X, Yang X, de Anda J, Huang J, Li D, Xu H, Shields KS, Džunková M, Hansen J, Patel IJ, Yee EU, Golenbock DT, Grant MA, Wong GCL, and Kelly CP
- Subjects
- Animals, Anti-Bacterial Agents adverse effects, Clostridioides difficile genetics, Clostridioides difficile metabolism, Clostridium Infections chemically induced, Clostridium Infections microbiology, Colitis chemically induced, Colitis microbiology, DNA, Bacterial metabolism, Disease Models, Animal, Female, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome immunology, Humans, Immunity, Innate, Mice, Mice, Knockout, Molecular Chaperones metabolism, Signal Transduction immunology, Toll-Like Receptor 9 genetics, Bacterial Toxins metabolism, Clostridioides difficile immunology, Clostridium Infections immunology, Colitis immunology, Enterotoxins metabolism, Toll-Like Receptor 9 metabolism
- Abstract
Background & Aims: Clostridioides difficile toxin A (TcdA) activates the innate immune response. TcdA co-purifies with DNA. Toll-like receptor 9 (TLR9) recognizes bacterial DNA to initiate inflammation. We investigated whether DNA bound to TcdA activates an inflammatory response in murine models of C difficile infection via activation of TLR9., Methods: We performed studies with human colonocytes and monocytes and macrophages from wild-type and TLR9 knockout mice incubated with TcdA or its antagonist (ODN TTAGGG) or transduced with vectors encoding TLR9 or small-interfering RNAs. Cytokine production was measured with enzyme-linked immunosorbent assay. We studied a transduction domain of TcdA (TcdA
57-80 ), which was predicted by machine learning to have cell-penetrating activity and confirmed by synchrotron small-angle X-ray scattering. Intestines of CD1 mice, C57BL6J mice, and mice that express a form of TLR9 that is not activated by CpG DNA were injected with TcdA, TLR9 antagonist, or both. Enterotoxicity was estimated based on loop weight to length ratios. A TLR9 antagonist was tested in mice infected with C difficile. We incubated human colon explants with an antagonist of TLR9 and measured TcdA-induced production of cytokines., Results: The TcdA57-80 protein transduction domain had membrane remodeling activity that allowed TcdA to enter endosomes. TcdA-bound DNA entered human colonocytes. TLR9 was required for production of cytokines by cultured cells and in human colon explants incubated with TcdA. TLR9 was required in TcdA-induced mice intestinal secretions and in the survival of mice infected by C difficile. Even in a protease-rich environment, in which only fragments of TcdA exist, the TcdA57-80 domain organized DNA into a geometrically ordered structure that activated TLR9., Conclusions: TcdA from C difficile can bind and organize bacterial DNA to activate TLR9. TcdA and TcdA fragments remodel membranes, which allows them to access endosomes and present bacterial DNA to and activate TLR9. Rather than inactivating the ability of DNA to bind TLR9, TcdA appears to chaperone and organize DNA into an inflammatory, spatially periodic structure., (Copyright © 2020 AGA Institute. All rights reserved.)- Published
- 2020
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13. Author Correction: Caspase-8 mediates inflammation and disease in rodent malaria.
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Pereira LMN, Assis PA, de Araújo NM, Durso DF, Junqueira C, Ataíde MA, Pereira DB, Lien E, Fitzgerald KA, Zamboni DS, Golenbock DT, and Gazzinelli RT
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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14. Integrative analysis of microRNA and mRNA expression profiles of monocyte-derived dendritic cells differentiation during experimental cerebral malaria.
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Assis PA, Fernandes Durso D, Chacon Cavalcante F, Zaniratto R, Carvalho-Silva AC, Cunha-Neto E, Golenbock DT, Rodrigues Pinto Ferreira L, and Tostes Gazzinelli R
- Subjects
- Animals, Dendritic Cells pathology, Malaria, Cerebral genetics, Malaria, Cerebral pathology, Mice, Mice, Knockout, MicroRNAs genetics, Monocytes pathology, RNA, Messenger genetics, Transcriptome immunology, Dendritic Cells immunology, Gene Expression Regulation immunology, Malaria, Cerebral immunology, MicroRNAs immunology, Monocytes immunology, Plasmodium berghei immunology, RNA, Messenger immunology
- Abstract
Heterogeneity and high plasticity are common features of cells from the mononuclear phagocyte system: monocytes (MOs), macrophages, and dendritic cells (DCs). Upon activation by microbial agents, MO can differentiate into MO-derived DCs (MODCs). In previous work, we have shown that during acute infection with Plasmodium berghei ANKA (PbA), MODCs become, transiently, the main CD11b
+ myeloid population in the spleen (SP) and once recruited to the brain play an important role in the development of experimental cerebral malaria (ECM). Here, we isolated 4 cell populations: bone marrow (BM) MOs (BM-MOs) and SP-MOs from uninfected mice; BM inflammatory MOs (BM-iMOs) and SP-MODCs from PbA-infected mice and used a system biology approach to a holistic transcriptomic comparison and provide an interactome analysis by integrating differentially expressed miRNAs (DEMs) and their differentially expressed gene targets (DEGs) data. The Jaccard index (JI) was used for gauging the similarity and diversity among these cell populations. Whereas BM-MOs, BM-iMOs, and SP-MOs presented high similarity of DEGs, SP-MODCs distinguished by showing a greater number of DEGs. Moreover, functional analysis identified an enrichment in canonical pathways, such as DC maturation, neuroinflammation, and IFN signaling. Upstream regulator analysis identified IFNγ as the potential upstream molecule that can explain the observed DEMs-Target DEGs intersections in SP-MODCs. Finally, directed target analysis and in vivo/ex vivo assays indicate that SP-MODCs differentiate in the SP and IFNγ is a main driver of this process., (©2020 Society for Leukocyte Biology.)- Published
- 2020
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15. Caspase-8 mediates inflammation and disease in rodent malaria.
- Author
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Pereira LMN, Assis PA, de Araújo NM, Durso DF, Junqueira C, Ataíde MA, Pereira DB, Lien E, Fitzgerald KA, Zamboni DS, Golenbock DT, and Gazzinelli RT
- Subjects
- Animals, Brain pathology, Caspase 1 metabolism, Dendritic Cells metabolism, Enzyme Activation, Extracellular Matrix metabolism, Gene Expression Regulation, Humans, Interferon-gamma metabolism, Interleukin-1beta metabolism, Lipopolysaccharides, Malaria, Cerebral genetics, Mice, Inbred C57BL, Monocytes metabolism, Plasmodium chabaudi physiology, Spleen metabolism, Toll-Like Receptors metabolism, Caspase 8 metabolism, Inflammation pathology, Malaria, Cerebral enzymology
- Abstract
Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1β and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.
- Published
- 2020
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16. The immunology of Plasmodium vivax malaria.
- Author
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Antonelli LR, Junqueira C, Vinetz JM, Golenbock DT, Ferreira MU, and Gazzinelli RT
- Subjects
- Adaptive Immunity, Antibodies, Protozoan immunology, Antigens, Protozoan immunology, Cytokines metabolism, Disease Susceptibility, Host-Parasite Interactions genetics, Humans, Immunity, Innate, Inflammation Mediators metabolism, Malaria Vaccines immunology, Malaria, Vivax genetics, Malaria, Vivax metabolism, Plasmodium vivax growth & development, Toll-Like Receptors metabolism, Host-Parasite Interactions immunology, Immunity, Malaria, Vivax immunology, Malaria, Vivax parasitology, Plasmodium vivax physiology
- Abstract
Plasmodium vivax infection, the predominant cause of malaria in Asia and Latin America, affects ~14 million individuals annually, with considerable adverse effects on wellbeing and socioeconomic development. A clinical hallmark of Plasmodium infection, the paroxysm, is driven by pyrogenic cytokines produced during the immune response. Here, we review studies on the role of specific immune cell types, cognate innate immune receptors, and inflammatory cytokines on parasite control and disease symptoms. This review also summarizes studies on recurrent infections in individuals living in endemic regions as well as asymptomatic infections, a serious barrier to eliminating this disease. We propose potential mechanisms behind these repeated and subclinical infections, such as poor induction of immunological memory cells and inefficient T effector cells. We address the role of antibody-mediated resistance to P. vivax infection and discuss current progress in vaccine development. Finally, we review immunoregulatory mechanisms, such as inhibitory receptors, T regulatory cells, and the anti-inflammatory cytokine, IL-10, that antagonizes both innate and acquired immune responses, interfering with the development of protective immunity and parasite clearance. These studies provide new insights for the clinical management of symptomatic as well as asymptomatic individuals and the development of an efficacious vaccine for vivax malaria., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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17. Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR.
- Author
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Deng M, Guo H, Tam JW, Johnson BM, Brickey WJ, New JS, Lenox A, Shi H, Golenbock DT, Koller BH, McKinnon KP, Beutler B, and Ting JP
- Subjects
- Animals, Calcium metabolism, Caspase 1 metabolism, Furans pharmacology, Heterocyclic Compounds, 4 or More Rings, Humans, Indenes, Interleukin-18 metabolism, Interleukin-1beta metabolism, Intracellular Signaling Peptides and Proteins metabolism, Mice, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Phosphate-Binding Proteins metabolism, Potassium metabolism, Sulfonamides pharmacology, Sulfones, Inflammasomes metabolism, NIMA-Related Kinases metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Platelet Activating Factor metabolism, Platelet Membrane Glycoproteins metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein-coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic., (© 2019 Deng et al.)
- Published
- 2019
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18. NLRP3 inflammasome activation drives tau pathology.
- Author
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Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, Griep A, Santarelli F, Brosseron F, Opitz S, Stunden J, Merten M, Kayed R, Golenbock DT, Blum D, Latz E, Buée L, and Heneka MT
- Subjects
- Animals, Cyclin-Dependent Kinase 5 metabolism, Gene Expression Regulation genetics, Humans, Inflammasomes genetics, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Phosphorylation, Protein Aggregation, Pathological physiopathology, tau Proteins genetics, Inflammasomes metabolism, Microglia pathology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, tau Proteins metabolism
- Abstract
Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline
1 . The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2 . Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3 , the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.- Published
- 2019
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19. The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2.
- Author
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Skjesol A, Yurchenko M, Bösl K, Gravastrand C, Nilsen KE, Grøvdal LM, Agliano F, Patane F, Lentini G, Kim H, Teti G, Kumar Sharma A, Kandasamy RK, Sporsheim B, Starheim KK, Golenbock DT, Stenmark H, McCaffrey M, Espevik T, and Husebye H
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Carrier Proteins physiology, Endocytosis, Endosomes, Escherichia coli pathogenicity, HEK293 Cells, Humans, Interferon Regulatory Factor-3, Lipopolysaccharides, Macrophages immunology, Macrophages metabolism, Membrane Proteins physiology, Mice, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, Primary Cell Culture, Protein Transport, Signal Transduction, Staphylococcus aureus pathogenicity, THP-1 Cells, Toll-Like Receptor 4 metabolism, cdc42 GTP-Binding Protein, rab GTP-Binding Proteins, rac1 GTP-Binding Protein, Adaptor Proteins, Signal Transducing physiology, Carrier Proteins metabolism, Membrane Proteins metabolism, Phagocytosis physiology
- Abstract
Phagocytosis is a complex process that eliminates microbes and is performed by specialised cells such as macrophages. Toll-like receptor 4 (TLR4) is expressed on the surface of macrophages and recognizes Gram-negative bacteria. Moreover, TLR4 has been suggested to play a role in the phagocytosis of Gram-negative bacteria, but the mechanisms remain unclear. Here we have used primary human macrophages and engineered THP-1 monocytes to show that the TLR4 sorting adapter, TRAM, is instrumental for phagocytosis of Escherichia coli as well as Staphylococcus aureus. We find that TRAM forms a complex with Rab11 family interacting protein 2 (FIP2) that is recruited to the phagocytic cups of E. coli. This promotes activation of the actin-regulatory GTPases Rac1 and Cdc42. Our results show that FIP2 guided TRAM recruitment orchestrates actin remodelling and IRF3 activation, two events that are both required for phagocytosis of Gram-negative bacteria., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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20. Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice.
- Author
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Tzeng TC, Hasegawa Y, Iguchi R, Cheung A, Caffrey DR, Thatcher EJ, Mao W, Germain G, Tamburro ND, Okabe S, Heneka MT, Latz E, Futai K, and Golenbock DT
- Subjects
- Alzheimer Disease drug therapy, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid genetics, Animals, Inflammasomes genetics, Interleukin-18 genetics, Interleukin-1beta genetics, Interleukin-1beta metabolism, Levetiracetam, Mice, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Piracetam analogs & derivatives, Piracetam pharmacology, Seizures drug therapy, Seizures genetics, Seizures pathology, Alzheimer Disease metabolism, Amyloid metabolism, Inflammasomes metabolism, Interleukin-18 metabolism, Seizures metabolism, Synaptic Transmission
- Abstract
Alzheimer's disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
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21. Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.
- Author
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Strangward P, Haley MJ, Albornoz MG, Barrington J, Shaw T, Dookie R, Zeef L, Baker SM, Winter E, Tzeng TC, Golenbock DT, Cruickshank SM, Allan SM, Craig A, Liew FY, Brough D, and Couper KN
- Subjects
- Animals, Brain metabolism, Brain pathology, Disease Models, Animal, Female, Gene Expression Profiling, Hemeproteins metabolism, Interleukin-1beta biosynthesis, Interleukin-33 antagonists & inhibitors, Macrophages metabolism, Macrophages pathology, Malaria, Cerebral metabolism, Malaria, Cerebral pathology, Malaria, Falciparum metabolism, Malaria, Falciparum pathology, Male, Mice, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Transcriptome drug effects, Antimalarials pharmacology, Brain parasitology, Drug Delivery Systems methods, Interleukin-33 metabolism, Malaria, Cerebral drug therapy, Malaria, Falciparum drug therapy, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Plasmodium falciparum metabolism
- Abstract
Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1β production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1β release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33-NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
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22. Daily Rhythms of TNFα Expression and Food Intake Regulate Synchrony of Plasmodium Stages with the Host Circadian Cycle.
- Author
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Hirako IC, Assis PA, Hojo-Souza NS, Reed G, Nakaya H, Golenbock DT, Coimbra RS, and Gazzinelli RT
- Subjects
- Animals, Carbohydrate Metabolism genetics, Cell Cycle immunology, Circadian Rhythm immunology, Diabetes Mellitus, Experimental, Disease Models, Animal, Eating, Energy Metabolism, Glucose metabolism, Host-Parasite Interactions immunology, Host-Parasite Interactions physiology, Hypoglycemia, Insulin metabolism, Interferon-gamma metabolism, Leukocytes metabolism, Leukocytes parasitology, Liver metabolism, Liver parasitology, Malaria immunology, Mice, Plasmodium pathogenicity, Plasmodium chabaudi pathogenicity, Receptors, Tumor Necrosis Factor, Trophozoites physiology, Circadian Rhythm physiology, Gene Expression Regulation, Malaria metabolism, Plasmodium physiology, Plasmodium chabaudi parasitology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism
- Abstract
The Plasmodium cell cycle, wherein millions of parasites differentiate and proliferate, occurs in synchrony with the vertebrate host's circadian cycle. The underlying mechanisms are unknown. Here we addressed this question in a mouse model of Plasmodium chabaudi infection. Inflammatory gene expression and carbohydrate metabolism are both enhanced in interferon-γ (IFNγ)-primed leukocytes and liver cells from P. chabaudi-infected mice. Tumor necrosis factor α (TNFα) expression oscillates across the host circadian cycle, and increased TNFα correlates with hypoglycemia and a higher frequency of non-replicative ring forms of trophozoites. Conversely, parasites proliferate and acquire biomass during food intake by the host. Importantly, cyclic hypoglycemia is attenuated and synchronization of P. chabaudi stages is disrupted in IFNγ
-/- , TNF receptor-/- , or diabetic mice. Hence, the daily rhythm of systemic TNFα production and host food intake set the pace for Plasmodium synchronization with the host's circadian cycle. This mechanism indicates that Plasmodium parasites take advantage of the host's feeding habits., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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23. Cutting Edge: Plasmodium falciparum Induces Trained Innate Immunity.
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Schrum JE, Crabtree JN, Dobbs KR, Kiritsy MC, Reed GW, Gazzinelli RT, Netea MG, Kazura JW, Dent AE, Fitzgerald KA, and Golenbock DT
- Subjects
- Child, Child, Preschool, Epigenesis, Genetic immunology, Female, Gene Expression Regulation immunology, Histones biosynthesis, Humans, Infant, Malaria, Falciparum metabolism, Male, Immunity, Innate immunology, Malaria, Falciparum immunology
- Abstract
Malarial infection in naive individuals induces a robust innate immune response. In the recently described model of innate immune memory, an initial stimulus primes the innate immune system to either hyperrespond (termed training) or hyporespond (tolerance) to subsequent immune challenge. Previous work in both mice and humans demonstrated that infection with malaria can both serve as a priming stimulus and promote tolerance to subsequent infection. In this study, we demonstrate that initial stimulation with Plasmodium falciparum -infected RBCs or the malaria crystal hemozoin induced human adherent PBMCs to hyperrespond to subsequent ligation of TLR2. This hyperresponsiveness correlated with increased H3K4me3 at important immunometabolic promoters, and these epigenetic modifications were also seen in Kenyan children naturally infected with malaria. However, the use of epigenetic and metabolic inhibitors indicated that the induction of trained immunity by malaria and its ligands may occur via a previously unrecognized mechanism(s)., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
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24. Cyclic GMP-AMP Synthase Is the Cytosolic Sensor of Plasmodium falciparum Genomic DNA and Activates Type I IFN in Malaria.
- Author
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Gallego-Marin C, Schrum JE, Andrade WA, Shaffer SA, Giraldo LF, Lasso AM, Kurt-Jones EA, Fitzgerald KA, and Golenbock DT
- Subjects
- Adolescent, Adult, Cells, Cultured, Erythrocytes metabolism, Erythrocytes parasitology, Female, Humans, Interferon Regulatory Factor-3 metabolism, Malaria, Falciparum metabolism, Malaria, Falciparum parasitology, Male, Membrane Proteins metabolism, Middle Aged, Nucleotides, Cyclic metabolism, Phosphorylation, Signal Transduction, Young Adult, DNA, Protozoan metabolism, Interferon Type I metabolism, Nucleotidyltransferases metabolism, Plasmodium falciparum genetics
- Abstract
Innate immune receptors have a key role in the sensing of malaria and initiating immune responses. As a consequence of infection, systemic inflammation emerges and is directly related to signs and symptoms during acute disease. We have previously reported that plasmodial DNA is the primary driver of systemic inflammation in malaria, both within the phagolysosome and in the cytosol of effector cells. In this article, we demonstrate that Plasmodium falciparum genomic DNA delivered to the cytosol of human monocytes binds and activates cyclic GMP-AMP synthase (cGAS). Activated cGAS synthesizes 2'3'-cGAMP, which we subsequently can detect using liquid chromatography-tandem mass spectrometry. 2'3'-cGAMP acts as a second messenger for STING activation and triggers TBK1/IRF3 activation, resulting in type I IFN production in human cells. This induction of type I IFN was independent of IFI16. Access of DNA to the cytosolic compartment is mediated by hemozoin, because incubation of purified malaria pigment with DNase abrogated IFN-β induction. Collectively, these observations implicate cGAS as an important cytosolic sensor of P. falciparum genomic DNA and reveal the role of the cGAS/STING pathway in the induction of type I IFN in response to malaria parasites., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
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25. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease.
- Author
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Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, Vieira-Saecker A, Schwartz S, Santarelli F, Kummer MP, Griep A, Gelpi E, Beilharz M, Riedel D, Golenbock DT, Geyer M, Walter J, Latz E, and Heneka MT
- Subjects
- Alzheimer Disease pathology, Amyloid beta-Protein Precursor deficiency, Amyloid beta-Protein Precursor genetics, Animals, Antibodies administration & dosage, Antibodies immunology, Antibodies pharmacology, CARD Signaling Adaptor Proteins antagonists & inhibitors, CARD Signaling Adaptor Proteins chemistry, CARD Signaling Adaptor Proteins immunology, Female, Hippocampus cytology, Hippocampus metabolism, Hippocampus pathology, Humans, Inflammasomes immunology, Inflammasomes metabolism, Inflammation metabolism, Inflammation pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Presenilin-1 deficiency, Presenilin-1 genetics, Protein Domains, Spatial Memory physiology, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, CARD Signaling Adaptor Proteins metabolism, Microglia metabolism, Protein Aggregation, Pathological
- Abstract
The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APP
Swe PSEN1dE9 mice. By contrast, homogenates from brains of APPSwe PSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwe PSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwe PSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.- Published
- 2017
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26. Activation of the NLRP3 inflammasome in microglia: the role of ceramide.
- Author
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Scheiblich H, Schlütter A, Golenbock DT, Latz E, Martinez-Martinez P, and Heneka MT
- Subjects
- Animals, Carrier Proteins metabolism, Cells, Cultured, Cytoskeletal Proteins metabolism, Interleukin-1beta metabolism, Macrophages metabolism, Mice, Microglia metabolism, Reactive Oxygen Species metabolism, Ceramides pharmacology, Inflammasomes drug effects, Inflammasomes metabolism, Microglia drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism
- Abstract
Inflammation within the CNS is a major component of many neurodegenerative diseases. A characteristic feature is the generation of microglia-derived factors that play an essential role in the immune response. IL-1β is a pro-inflammatory cytokine released by activated microglia, able to exacerbate injury at elevated levels. In the presence of caspase-1, pro-IL-1β is cleaved to the mature cytokine following NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation. Growing evidence suggests that ceramide plays a critical role in NLRP3 inflammasome assembly, however, the relationship between ceramide and inflammasome activation in microglia remains unknown. Here, we investigated potential mechanistic links between ceramide as a modulator of NLRP3 inflammasome assembly and the resulting secretion of IL-1β using small bioactive enzyme stimulators and inhibitors of ceramide signaling in wild-type and apoptosis-associated speck-like protein containing a CARD knockout (ASC
-/- ) primary microglia. To induce the expression of inflammasome components, microglia were primed prior to experiments. Treatment with sodium palmitate (PA) induced de novo ceramide synthesis via modulation of its synthesizing protein serine palmitoyl transferase resulting in increased IL-1β secretion in microglia. Exposure of microglia to the serine palmitoyl transferase-inhibitor l-cycloserine significantly prevented PA-induced IL-1β secretion. Application of the ceramide analogue C2 and the sphingosine-1-phosphate-receptor agonist Fingolimod (FTY720) up-regulated levels of IL-1β and cleaved caspase-1 in wild-type microglia, whereas ASC-/- microglia were unaffected. HPA-12 inhibition of ceramide transport did not affect inflammasome activation. Taken together, our findings reveal a critical role for ceramide as a positive modulator of NLRP3 inflammasome assembly and the resulting release of IL-1β., (© 2017 International Society for Neurochemistry.)- Published
- 2017
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27. miR-718 represses proinflammatory cytokine production through targeting phosphatase and tensin homolog (PTEN).
- Author
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Kalantari P, Harandi OF, Agarwal S, Rus F, Kurt-Jones EA, Fitzgerald KA, Caffrey DR, and Golenbock DT
- Subjects
- Animals, Cytokines genetics, Gonorrhea genetics, Gonorrhea metabolism, Humans, Interleukin-1 Receptor-Associated Kinases genetics, Interleukin-1 Receptor-Associated Kinases metabolism, Macrophages microbiology, Macrophages pathology, Mice, Mice, Knockout, MicroRNAs genetics, Neisseria gonorrhoeae metabolism, PTEN Phosphohydrolase genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Toll-Like Receptor 3 genetics, Toll-Like Receptor 3 metabolism, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, 5' Untranslated Regions, Cytokines metabolism, Macrophages metabolism, MicroRNAs metabolism, PTEN Phosphohydrolase metabolism, Signal Transduction
- Abstract
Bacterial sepsis involves a complex interaction between the host immune response and bacterial LPS. LPS binds Toll-like receptor (TLR) 4, which leads to the release of proinflammatory cytokines that are essential for a potent innate immune response against pathogens. The innate immune system is tightly regulated, as excessive inflammation can lead to organ failure and death. MicroRNAs have recently emerged as important regulators of the innate immune system. Here we determined the function of miR-718, which is conserved across mammals and overlaps with the 5' UTR of the interleukin 1 receptor-associated kinase ( IRAK1 ) gene. As IRAK1 is a key component of innate immune signaling pathways that are downstream of most TLRs, we hypothesized that miR-718 helps regulate the innate immune response. Activation of TLR4, but not TLR3, induced the expression of miR-718 in macrophages. miR-718 expression was also induced in the spleens of mice upon LPS injection. miR-718 modulates PI3K/Akt signaling by directly down-regulating phosphatase and tensin homolog (PTEN), thereby promoting phosphorylation of Akt, which leads to a decrease in proinflammatory cytokine production. Phosphorylated Akt induces let-7e expression, which, in turn, down-regulates TLR4 and further diminishes TLR4-mediated proinflammatory signals. Decreased miR-718 expression is associated with bacterial burden during Neisseria gonorrhoeae infection and alters the infection dynamics of N. gonorrhoeae in vitro Furthermore, miR-718 regulates the induction of LPS tolerance in macrophages. We propose a role for miR-718 in controlling TLR4 signaling and inflammatory cytokine signaling through a negative feedback regulation loop involving down-regulation of TLR4, IRAK1, and NF-κB., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
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28. Control of the innate immune response by the mevalonate pathway.
- Author
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Akula MK, Shi M, Jiang Z, Foster CE, Miao D, Li AS, Zhang X, Gavin RM, Forde SD, Germain G, Carpenter S, Rosadini CV, Gritsman K, Chae JJ, Hampton R, Silverman N, Gravallese EM, Kagan JC, Fitzgerald KA, Kastner DL, Golenbock DT, Bergo MO, and Wang D
- Subjects
- Alkyl and Aryl Transferases genetics, Animals, Cells, Cultured, Familial Mediterranean Fever genetics, Humans, Immunity, Innate, Interleukin-1beta metabolism, Mice, Inbred C57BL, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics, Polyisoprenyl Phosphates metabolism, Protein Processing, Post-Translational, Signal Transduction, Toll-Like Receptors metabolism, Alkyl and Aryl Transferases metabolism, Familial Mediterranean Fever metabolism, Inflammasomes metabolism, Macrophages physiology, Mutation genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Pyrin genetics
- Abstract
Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.
- Published
- 2016
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29. Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production.
- Author
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Andrade WA, Firon A, Schmidt T, Hornung V, Fitzgerald KA, Kurt-Jones EA, Trieu-Cuot P, Golenbock DT, and Kaminski PA
- Subjects
- Biotransformation, Streptococcus agalactiae enzymology, Dinucleoside Phosphates metabolism, Immune Evasion, Interferon Type I metabolism, Membrane Proteins metabolism, Pyrophosphatases metabolism, Streptococcus agalactiae immunology, Streptococcus agalactiae metabolism
- Abstract
Induction of type I interferon (IFN) in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP. Inactivation of CdnP leads to c-di-AMP accumulation outside the bacteria and increased IFN-β production. Higher IFN-β levels in vivo increase GBS killing by the host. The IFN-β overproduction observed in the absence of CdnP is due to the cumulative effect of DNA sensing by cGAS and STING-dependent sensing of c-di-AMP. These findings describe the importance of a bacterial c-di-AMP ectonucleotidase and suggest a direct bacterial mechanism that dampens activation of the cGAS-STING axis., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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30. A Fluorescent Reporter Mouse for Inflammasome Assembly Demonstrates an Important Role for Cell-Bound and Free ASC Specks during In Vivo Infection.
- Author
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Tzeng TC, Schattgen S, Monks B, Wang D, Cerny A, Latz E, Fitzgerald K, and Golenbock DT
- Subjects
- Animals, CARD Signaling Adaptor Proteins biosynthesis, Female, Gene Expression, Genes, Reporter, Male, Mice, Inbred C57BL, Mice, Transgenic, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections metabolism, Peritonitis immunology, Peritonitis metabolism, Protein Multimerization, Streptococcal Infections immunology, Streptococcal Infections metabolism, CARD Signaling Adaptor Proteins genetics, Inflammasomes metabolism
- Abstract
Inflammasome activation is associated with numerous diseases. However, in vivo detection of the activated inflammasome complex has been limited by a dearth of tools. We have developed transgenic mice that ectopically express the fluorescent adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and characterized the formation of assembled inflammasome complexes ("specks") in primary cells and tissues. In addition to hematopoietic cells, we have found that a stromal population in the lung tissues formed specks during the early phase of influenza infection, whereas myeloid cells showed speck formation after 2 days. In a peritonitis and group B streptococcus infection model, a higher percentage of neutrophils formed specks at early phases of infection, while dendritic cells formed specks at later time points. Furthermore, speck-forming cells underwent pyroptosis and extensive release of specks to the extracellular milieu in vivo. These data underscore the importance of free specks during inflammatory processes in vivo., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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31. Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4.
- Author
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Andrade WA, Agarwal S, Mo S, Shaffer SA, Dillard JP, Schmidt T, Hornung V, Fitzgerald KA, Kurt-Jones EA, and Golenbock DT
- Subjects
- Bacterial Secretion Systems, Cell Line, DNA, Bacterial metabolism, Humans, Iron metabolism, Membrane Proteins metabolism, Microbial Viability, Nucleotides, Cyclic metabolism, Transfection, Interferon Type I metabolism, Neisseria gonorrhoeae physiology, Nucleotidyltransferases metabolism, Toll-Like Receptor 4 metabolism
- Abstract
The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS(-/-) and TLR4(-/-) cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection., (Copyright © 2016. Published by Elsevier Inc.)
- Published
- 2016
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32. A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae.
- Author
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Shaughnessy J, Gulati S, Agarwal S, Unemo M, Ohnishi M, Su XH, Monks BG, Visintin A, Madico G, Lewis LA, Golenbock DT, Reed GW, Rice PA, and Ram S
- Subjects
- Animals, Complement Factor H pharmacology, Disease Models, Animal, Female, Flow Cytometry, Humans, Immunoglobulin Fc Fragments pharmacology, Mice, Mice, Inbred BALB C, Neisseria gonorrhoeae immunology, Recombinant Fusion Proteins pharmacology, Complement Factor H immunology, Gonorrhea immunology, Immunoglobulin Fc Fragments immunology, Immunotherapy methods, Recombinant Fusion Proteins immunology
- Abstract
Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including N. gonorrhoeae, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains 18-20 (FH18-20). We explored the use of fusing FH18-20 with IgG Fc (FH18-20/Fc) to create a novel anti-infective immunotherapeutic. FH18-20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18-20 that eliminated complement activation on host cells, yet maintained binding to N. gonorrhoeae, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. One of the mutant proteins (D to G at position 1119 in domain 19; FHD1119G/Fc) facilitated complement-dependent killing of gonococci similar to unmodified FH18-20/Fc but, unlike FH18-20/Fc, did not lyse human erythrocytes. FHD1119G/Fc bound to all (100%) of 15 sialylated clinical N. gonorrhoeae isolates tested (including three contemporary ceftriaxone-resistant strains), mediated complement-dependent killing of 10 of 15 (67%) strains, and enhanced C3 deposition (≥10-fold above baseline levels) on each of the five isolates not directly killed by complement. FHD1119G/Fc facilitated opsonophagocytic killing of a serum-resistant strain by human polymorphonuclear neutrophils. FHD1119G/Fc administered intravaginally significantly reduced the duration and burden of gonococcal infection in the mouse vaginal colonization model. FHD1119G/Fc represents a novel immunotherapeutic against multidrug-resistant N. gonorrhoeae., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
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33. Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria.
- Author
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Rocha BC, Marques PE, Leoratti FMS, Junqueira C, Pereira DB, Antonelli LRDV, Menezes GB, Golenbock DT, and Gazzinelli RT
- Subjects
- Animals, Granulocytes pathology, Humans, Interferon Type I biosynthesis, Interferon Type I genetics, Malaria metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils pathology, Signal Transduction, Granulocytes metabolism, Interferon Type I metabolism, Malaria genetics, Malaria pathology, Neutrophils metabolism, Transcription, Genetic genetics
- Abstract
Neutrophils are the most abundant leukocyte population in the bloodstream, the primary compartment of Plasmodium sp. infection. However, the role of these polymorphonuclear cells in mediating either the resistance or the pathogenesis of malaria is poorly understood. We report that circulating neutrophils from malaria patients are highly activated, as indicated by a strong type I interferon transcriptional signature, increased expression of surface activation markers, enhanced release of reactive oxygen species and myeloperoxidase, and a high frequency of low-density granulocytes. The activation of neutrophils was associated with increased levels of serum alanine and aspartate aminotransferases, indicating liver damage. In a rodent malaria model, we observed intense recruitment of neutrophils to liver sinusoids. Neutrophil migration and IL-1β and chemokine expression as well as liver damage were all dependent on type I interferon signaling. The data suggest that type I interferon signaling has a central role in neutrophil activation and malaria pathogenesis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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34. LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA-I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux.
- Author
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Tamehiro N, Park MH, Hawxhurst V, Nagpal K, Adams ME, Zannis VI, Golenbock DT, and Fitzgerald ML
- Subjects
- ATP Binding Cassette Transporter 1 deficiency, ATP Binding Cassette Transporter 1 genetics, Animals, Biological Transport, Active, Calcium-Binding Proteins deficiency, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Cell Line, Dystrophin-Associated Proteins deficiency, Dystrophin-Associated Proteins genetics, Hydrocarbons, Fluorinated pharmacology, Lipid Metabolism, Liver X Receptors, Macrophages drug effects, Membrane Proteins deficiency, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Multiprotein Complexes chemistry, Multiprotein Complexes metabolism, Muscle Proteins deficiency, Muscle Proteins genetics, Muscle Proteins metabolism, Protein Binding, Protein Interaction Domains and Motifs, Protein Stability, RNA, Messenger genetics, RNA, Messenger metabolism, Sulfonamides pharmacology, Up-Regulation, ATP Binding Cassette Transporter 1 metabolism, Apolipoprotein A-I metabolism, Dystrophin-Associated Proteins metabolism, Macrophages metabolism, Orphan Nuclear Receptors agonists
- Abstract
Macrophage ABCA1 effluxes lipid and has anti-inflammatory activity. The syntrophins, which are cytoplasmic PDZ protein scaffolding factors, can bind ABCA1 and modulate its activity. However, many of the data assessing the function of the ABCA1-syntrophin interaction are based on overexpression in nonmacrophage cells. To assess endogenous complex function in macrophages, we derived immortalized macrophages from Abca1(+/+) and Abca1(-/-) mice and show their phenotype recapitulates primary macrophages. Abca1(+/+) lines express the CD11B and F4/80 macrophage markers and markedly upregulate cholesterol efflux in response to LXR nuclear hormone agonists. In contrast, immortalized Abca1(-/-) macrophages show no efflux to apoA-I. In response to LPS, Abca1(-/-) macrophages display pro-inflammatory changes, including an increased level of expression of cell surface CD14, and 11-26-fold higher levels of IL-6 and IL-12 mRNA. Given recapitulation of phenotype, we show with these lines that the ABCA1-syntrophin protein complex is upregulated by LXR agonists and can bind apoA-I. Moreover, in immortalized macrophages, combined α1/β2-syntrophin loss modulated ABCA1 cell surface levels and induced pro-inflammatory gene expression. However, loss of all three syntrophin isoforms known to bind ABCA1 did not impair lipid efflux in immortalized or primary macrophages. Thus, the ABCA1-syntrophin protein complex is not essential for ABCA1 macrophage lipid efflux but does directly interact with apoA-I and can modulate the pool of cell surface ABCA1 stabilized by apoA-I.
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- 2015
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35. DNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14+ CD16+ CD64high CD32low Inflammatory Monocytes from Malaria Patients.
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Hirako IC, Gallego-Marin C, Ataide MA, Andrade WA, Gravina H, Rocha BC, de Oliveira RB, Pereira DB, Vinetz J, Diamond B, Ram S, Golenbock DT, and Gazzinelli RT
- Subjects
- Antigen-Antibody Complex blood, Antigens, CD analysis, Humans, Immunophenotyping, Malaria, Falciparum immunology, Malaria, Vivax immunology, Monocytes chemistry, Protein Multimerization, Antigen-Antibody Complex metabolism, Cytokines metabolism, DNA, Protozoan immunology, Inflammasomes metabolism, Malaria, Falciparum pathology, Malaria, Vivax pathology, Monocytes metabolism
- Abstract
Unlabelled: High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-κB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcγRIIIA)(+) CD64 (FcγRI)(high) CD32 (FcγRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) CD16(-)) that produces high levels of IL-10 and lower levels of TNF-α and IL-1β in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases., Importance: Every year, there are approximately 200 million cases of Plasmodium falciparum and P. vivax malaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodium species. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing Plasmodium DNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease., (Copyright © 2015 Hirako et al.)
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- 2015
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36. Neuroinflammation in Alzheimer's disease.
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Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, and Kummer MP
- Subjects
- Animals, Astrocytes immunology, Astrocytes pathology, Biomarkers blood, Biomarkers cerebrospinal fluid, Brain Injuries metabolism, Clinical Trials as Topic, Disease Models, Animal, Disease Progression, Humans, Immunization, Inflammation diagnosis, Inflammation immunology, Inflammation Mediators immunology, Locus Coeruleus pathology, Nootropic Agents administration & dosage, Obesity metabolism, Phagocytosis, Protein Folding, Risk Factors, Severity of Illness Index, Alzheimer Disease genetics, Alzheimer Disease immunology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease prevention & control, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Brain Injuries complications, Immunity, Innate, Inflammation metabolism, Inflammation Mediators metabolism, Microglia immunology, Microglia pathology, Obesity complications
- Abstract
Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
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- 2015
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37. Involvement of Nod2 in the innate immune response elicited by malarial pigment hemozoin.
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Corbett Y, Parapini S, D'Alessandro S, Scaccabarozzi D, Rocha BC, Egan TJ, Omar A, Galastri L, Fitzgerald KA, Golenbock DT, Taramelli D, and Basilico N
- Subjects
- Animals, Cytokines metabolism, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout immunology, Hemeproteins immunology, Malaria immunology, Nod2 Signaling Adaptor Protein immunology
- Abstract
In malaria, the evidence concerning the nucleotide-binding, oligomerization domain (NOD) 2 (NOD2) receptor is fragmented and the stimuli that might activate NOD2 are not well characterized. We investigated the role of NOD2 in vitro in the response of macrophages to Plasmodium falciparum products. Immortalized or primary bone marrow derived macrophages from wild type C57Bl/6 mice, or knockout mice for NOD2 or its adaptor proteins, were either primed with interferon gamma or left untreated, and stimulated with parasite products. Both lysates of infected erythrocytes or hemozoin induced higher levels of nitric oxide in primed than in unprimed wild type macrophages. When stimulated with hemozoin, primed macrophages knockout for NOD2, or for its adaptor proteins, produced significantly lower nitric oxide levels compared to wild type cells. Differently from hemozoin, the use of β-hematin (synthetic hemozoin) as stimulus showed that NOD2 is dispensable. Furthermore, the production of inflammatory cytokines by wild type cells treated with hemozoin was not dependent on NOD2. These data indicate that parasite components present in the hemozoin, differently from β-hematin, induce the production of nitric oxide through the activation of NOD2, whereas the production of inflammatory cytokines, like TNF-α or MIP-2 (CXCL2), seems to be NOD2 independent., (Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)
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- 2015
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38. Innate immunity in Alzheimer's disease.
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Heneka MT, Golenbock DT, and Latz E
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- Animals, Humans, Inflammation immunology, Alzheimer Disease immunology, Immunity, Innate immunology
- Abstract
Alzheimer's disease (AD) is the world's most common dementing illness, affecting over 150 million patients. Classically AD has been viewed as a neurodegenerative disease of the elderly, characterized by the extracellular deposition of misfolded amyloid-β (Aβ) peptide and the intracellular formation of neurofibrillary tangles. Only recently has neuroinflammation emerged as an important component of AD pathology. Experimental, genetic and epidemiological data now indicate a crucial role for activation of the innate immune system as a disease-promoting factor. The sustained formation and deposition of Aβ aggregates causes chronic activation of the immune system and disturbance of microglial clearance functions. Here we review advances in the molecular understanding of the inflammatory response in AD that point to novel therapeutic approaches for the treatment of this devastating disease.
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- 2015
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39. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling.
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Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE, Golenbock DT, Meng J, Roth J, Chavan SS, Andersson U, Billiar TR, Tracey KJ, and Al-Abed Y
- Subjects
- Acetaminophen, Animals, Blotting, Western, Cell Line, Cell Line, Tumor, Cells, Cultured, Chemical and Drug Induced Liver Injury blood, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury metabolism, Cytokines blood, Cytokines pharmacology, Disulfides metabolism, HMGB1 Protein pharmacology, Lipopolysaccharides pharmacology, Lymphocyte Antigen 96 chemistry, Lymphocyte Antigen 96 genetics, Macrophages drug effects, Macrophages metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Models, Molecular, Peptides chemistry, Peptides metabolism, Peptides pharmacology, Protein Binding drug effects, Protein Structure, Tertiary, RNA Interference, Reperfusion Injury blood, Reperfusion Injury metabolism, Survival Analysis, HMGB1 Protein metabolism, Lymphocyte Antigen 96 metabolism, Signal Transduction, Toll-Like Receptor 4 metabolism
- Abstract
Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2-HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4-MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness., (© 2015 Yang et al.)
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- 2015
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40. Innate sensing of malaria parasites.
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Gazzinelli RT, Kalantari P, Fitzgerald KA, and Golenbock DT
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- DNA, Protozoan immunology, Erythrocytes parasitology, Hemeproteins immunology, Humans, Macrophages immunology, Malaria Vaccines immunology, Malaria, Falciparum pathology, Plasmodium falciparum genetics, RNA, Protozoan immunology, Immunity, Innate, Malaria, Falciparum immunology, Plasmodium falciparum immunology
- Abstract
Innate immune receptors have a key role in immune surveillance by sensing microorganisms and initiating protective immune responses. However, the innate immune system is a classic 'double-edged sword' that can overreact to pathogens, which can have deleterious effects and lead to clinical manifestations. Recent studies have unveiled the complexity of innate immune receptors that function as sensors of Plasmodium spp. in the vertebrate host. This Review highlights the cellular and molecular mechanisms by which Plasmodium infection is sensed by different families of innate immune receptors. We also discuss how these events mediate both host resistance to infection and the pathogenesis of malaria.
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- 2014
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41. Hemolysis-induced lethality involves inflammasome activation by heme.
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Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, Zamboni DS, and Bozza MT
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- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Caspase 1 deficiency, Caspase 1 genetics, Caspase 1 metabolism, Heme chemistry, Heme immunology, Hemolysis immunology, Humans, Inflammasomes immunology, Interleukin-1beta metabolism, Macrophage Activation, Macrophages immunology, Macrophages metabolism, Male, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, NADPH Oxidase 2, NADPH Oxidases metabolism, NLR Family, Pyrin Domain-Containing 3 Protein, Potassium metabolism, Protoporphyrins chemistry, Protoporphyrins metabolism, Reactive Oxygen Species metabolism, Heme metabolism, Hemolysis physiology, Inflammasomes metabolism
- Abstract
The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. We found that heme, but not porphyrins without iron, activated LPS-primed macrophages promoting the processing of IL-1β dependent on nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3). The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K(+) efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.
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- 2014
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42. The CD14+CD16+ inflammatory monocyte subset displays increased mitochondrial activity and effector function during acute Plasmodium vivax malaria.
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Antonelli LR, Leoratti FM, Costa PA, Rocha BC, Diniz SQ, Tada MS, Pereira DB, Teixeira-Carvalho A, Golenbock DT, Gonçalves R, and Gazzinelli RT
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Female, Flow Cytometry, Humans, Immunophenotyping, Malaria, Vivax metabolism, Malaria, Vivax parasitology, Male, Middle Aged, Mitochondria metabolism, Mitochondria pathology, Monocytes metabolism, Monocytes parasitology, Phagocytosis, Reactive Oxygen Species metabolism, Young Adult, Erythrocytes immunology, Inflammation immunology, Lipopolysaccharide Receptors immunology, Malaria, Vivax immunology, Mitochondria immunology, Monocytes immunology, Plasmodium vivax immunology, Receptors, IgG immunology
- Abstract
Infection with Plasmodium vivax results in strong activation of monocytes, which are important components of both the systemic inflammatory response and parasite control. The overall goal of this study was to define the role of monocytes during P. vivax malaria. Here, we demonstrate that P. vivax-infected patients display significant increase in circulating monocytes, which were defined as CD14(+)CD16- (classical), CD14(+)CD16(+) (inflammatory), and CD14loCD16(+) (patrolling) cells. While the classical and inflammatory monocytes were found to be the primary source of pro-inflammatory cytokines, the CD16(+) cells, in particular the CD14(+)CD16(+) monocytes, expressed the highest levels of activation markers, which included chemokine receptors and adhesion molecules. Morphologically, CD14(+) were distinguished from CD14lo monocytes by displaying larger and more active mitochondria. CD14(+)CD16(+) monocytes were more efficient in phagocytizing P. vivax-infected reticulocytes, which induced them to produce high levels of intracellular TNF-α and reactive oxygen species. Importantly, antibodies specific for ICAM-1, PECAM-1 or LFA-1 efficiently blocked the phagocytosis of infected reticulocytes by monocytes. Hence, our results provide key information on the mechanism by which CD14(+)CD16(+) cells control parasite burden, supporting the hypothesis that they play a role in resistance to P. vivax infection.
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- 2014
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43. 3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1β interferes with mature IL-1β signaling.
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Davaro F, Forde SD, Garfield M, Jiang Z, Halmen K, Tamburro ND, Kurt-Jones E, Fitzgerald KA, Golenbock DT, and Wang D
- Subjects
- Animals, Cells, Cultured, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Interleukin-1beta metabolism, Signal Transduction drug effects
- Abstract
Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1β (IL-1β) is synthesized as a non-active precursor. The 31-kDa pro-IL-1β is processed into the 17-kDa active form by caspase-1-activating inflammasomes. Here, we report a novel signaling pathway induced by statins, which leads to processing of pro-IL-1β into an intermediate 28-kDa form. This statin-induced IL-1β processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1β cannot activate interleukin-1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1β signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1β. These results may provide new clues to explain the anti-inflammatory effects of statins., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
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- 2014
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44. RNA and β-hemolysin of group B Streptococcus induce interleukin-1β (IL-1β) by activating NLRP3 inflammasomes in mouse macrophages.
- Author
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Gupta R, Ghosh S, Monks B, DeOliveira RB, Tzeng TC, Kalantari P, Nandy A, Bhattacharjee B, Chan J, Ferreira F, Rathinam V, Sharma S, Lien E, Silverman N, Fitzgerald K, Firon A, Trieu-Cuot P, Henneke P, and Golenbock DT
- Subjects
- Animals, Humans, Interleukin-1beta metabolism, Lysosomes metabolism, Lysosomes microbiology, Macrophages cytology, Macrophages microbiology, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Phagosomes metabolism, Phagosomes microbiology, Streptococcus agalactiae metabolism, Bacterial Proteins metabolism, Carrier Proteins metabolism, Hemolysin Proteins metabolism, Inflammasomes metabolism, Interleukin-1beta biosynthesis, Macrophages metabolism, RNA, Bacterial metabolism, Streptococcus agalactiae physiology
- Abstract
The inflammatory cytokine IL-1β is critical for host responses against many human pathogens. Here, we define Group B Streptococcus (GBS)-mediated activation of the Nod-like receptor-P3 (NLRP3) inflammasome in macrophages. NLRP3 activation requires GBS expression of the cytolytic toxin, β-hemolysin, lysosomal acidification, and leakage. These processes allow the interaction of GBS RNA with cytosolic NLRP3. The present study supports a model in which GBS RNA, along with lysosomal components including cathepsins, leaks out of lysosomes and interacts with NLRP3 to induce IL-1β production., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
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- 2014
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45. Increased survival in B-cell-deficient mice during experimental cerebral malaria suggests a role for circulating immune complexes.
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de Oliveira RB, Wang JP, Ram S, Gazzinelli RT, Finberg RW, and Golenbock DT
- Subjects
- Animals, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Complement 3b genetics, Receptors, Complement 3b immunology, Survival Analysis, Antigen-Antibody Complex immunology, Antigen-Antibody Complex toxicity, B-Lymphocytes immunology, Malaria, Cerebral immunology, Malaria, Cerebral pathology, Plasmodium berghei immunology
- Abstract
The pathogenesis of malaria, an insect-borne disease that takes millions of lives every year, is still not fully understood. Complement receptor 1 (CR1) has been described as a receptor for Plasmodium falciparum, which causes cerebral malaria in humans. We investigated the role of CR1 in an experimental model of cerebral malaria. Transgenic mice expressing human CR1 (hCR1(+)) on erythrocytes were infected with Plasmodium berghei ANKA and developed cerebral malaria. No difference in survival was observed in hCR1(+) mice compared to wild-type mice following infection with P. berghei ANKA; however, hCR1 detection was significantly diminished on erythrocytes between days 7 and 10 postinfection. hCR1 levels returned to baseline by day 17 postinfection in surviving animals. Immunoblot assays revealed that total erythrocyte hCR1 levels were diminished, confirming that immune complexes in association with erythrocyte hCR1 were likely removed from erythrocytes in vivo by clearance following immune adherence. Decreases in hCR1 were completely dependent on C3 expression, as mice treated with cobra venom factor (which consumes and depletes C3) retained hCR1 on erythrocytes during C3 depletion through day 7; erythrocyte hCR1 decreases were observed only when C3 levels recovered on day 9. B-cell-deficient mice exhibit a marked increase in survival following infection with P. berghei ANKA, which suggests that immune complexes play a central role in the pathogenesis of experimental cerebral malaria. Together, our findings highlight the importance of complement and immune complexes in experimental cerebral malaria. IMPORTANCE Cerebral malaria is a deadly complication of infection with Plasmodium falciparum. Despite its high prevalence, relatively little is understood about its pathogenesis. We have determined that immune complexes are generated and deposited on erythrocytes specifically expressing human complement receptor 1 in a mouse model of cerebral malaria. We also provide evidence demonstrating the importance of immunoglobulins in the pathogenesis of cerebral malaria in mice. These findings may have important implications in human cerebral malaria.
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- 2014
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46. TRIF signaling is essential for TLR4-driven IgE class switching.
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Janssen E, Ozcan E, Liadaki K, Jabara HH, Manis J, Ullas S, Akira S, Fitzgerald KA, Golenbock DT, and Geha RS
- Subjects
- Adaptor Proteins, Vesicular Transport genetics, Adaptor Proteins, Vesicular Transport metabolism, Animals, B-Lymphocytes drug effects, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Survival drug effects, Cell Survival genetics, Cell Survival immunology, Cytidine Deaminase genetics, Cytidine Deaminase immunology, Cytidine Deaminase metabolism, Immunoblotting, Immunoglobulin Class Switching drug effects, Immunoglobulin E genetics, Immunoglobulin E metabolism, Immunoglobulin G genetics, Immunoglobulin G immunology, Immunoglobulin G metabolism, Immunoglobulin epsilon-Chains genetics, Immunoglobulin epsilon-Chains immunology, Immunoglobulin epsilon-Chains metabolism, Immunoglobulin gamma-Chains genetics, Immunoglobulin gamma-Chains immunology, Immunoglobulin gamma-Chains metabolism, Interleukin-4 immunology, Interleukin-4 pharmacology, Lipopolysaccharides immunology, Lipopolysaccharides pharmacology, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 immunology, Myeloid Differentiation Factor 88 metabolism, Phenylenediamines immunology, Phenylenediamines pharmacology, Receptors, Interleukin genetics, Receptors, Interleukin immunology, Receptors, Interleukin metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Signal Transduction genetics, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 metabolism, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelA immunology, Transcription Factor RelA metabolism, Adaptor Proteins, Vesicular Transport immunology, Immunoglobulin Class Switching immunology, Immunoglobulin E immunology, Signal Transduction immunology, Toll-Like Receptor 4 immunology
- Abstract
The TLR4 ligand LPS causes mouse B cells to undergo IgE and IgG1 isotype switching in the presence of IL-4. TLR4 activates two signaling pathways mediated by the adaptor molecules MyD88 and Toll/IL-IR domain-containing adapter-inducing IFN-β (TRIF)-related adaptor molecule (TRAM), which recruits TRIF. Following stimulation with LPS plus IL-4, Tram(-/-) and Trif(-/-) B cells completely failed to express Cε germline transcripts (GLT) and secrete IgE. In contrast, Myd88(-/-) B cells had normal expression of Cε GLT but reduced IgE secretion in response to LPS plus IL-4. Following LPS plus IL-4 stimulation, Cγ1 GLT expression was modestly reduced in Tram(-/-) and Trif(-/-) B cells, whereas Aicda expression and IgG1 secretion were reduced in Tram(-/-), Trif(-/-), and Myd88(-/-) B cells. B cells from all strains secreted normal amounts of IgE and IgG1 in response to anti-CD40 plus IL-4. Following stimulation with LPS plus IL-4, Trif(-/-) B cells failed to sustain NF-κB p65 nuclear translocation beyond 3 h and had reduced binding of p65 to the Iε promoter. Addition of the NF-κB inhibitor, JSH-23, to wild-type B cells 15 h after LPS plus IL-4 stimulation selectively blocked Cε GLT expression and IgE secretion but had little effect on Cγ1 GLT expression and IgG secretion. These results indicate that sustained activation of NF-κB driven by TRIF is essential for LPS plus IL-4-driven activation of the Cε locus and class switching to IgE.
- Published
- 2014
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47. Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria.
- Author
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Kalantari P, DeOliveira RB, Chan J, Corbett Y, Rathinam V, Stutz A, Latz E, Gazzinelli RT, Golenbock DT, and Fitzgerald KA
- Subjects
- Animals, Carrier Proteins genetics, Cells, Cultured, DNA, Protozoan pharmacology, DNA-Binding Proteins, Erythrocytes drug effects, Erythrocytes metabolism, Erythrocytes parasitology, Hemeproteins pharmacology, Humans, Inflammasomes genetics, Interleukin-1beta genetics, Interleukin-1beta metabolism, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Nuclear Proteins genetics, Phagocytosis, Plasmodium pathogenicity, Toll-Like Receptor 9 metabolism, Carrier Proteins metabolism, DNA, Protozoan metabolism, Hemeproteins metabolism, Inflammasomes metabolism, Malaria metabolism, Nuclear Proteins metabolism
- Abstract
Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and DNA dissociate. Hz subsequently induces phagolysosomal destabilization, allowing phagolysosomal contents access to the cytosol, where DNA receptors become activated. Similar observations were made with Plasmodium-infected RBCs. Finally, infected erythrocytes activated both the NLRP3 and AIM2 inflammasomes. These observations suggest that Hz and DNA work together to induce systemic inflammation during malaria., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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48. Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.
- Author
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Liehl P, Zuzarte-Luís V, Chan J, Zillinger T, Baptista F, Carapau D, Konert M, Hanson KK, Carret C, Lassnig C, Müller M, Kalinke U, Saeed M, Chora AF, Golenbock DT, Strobl B, Prudêncio M, Coelho LP, Kappe SH, Superti-Furga G, Pichlmair A, Vigário AM, Rice CM, Fitzgerald KA, Barchet W, and Mota MM
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Blotting, Western, DEAD-box RNA Helicases immunology, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression Profiling, Green Fluorescent Proteins, Immunohistochemistry, Interferon Regulatory Factor-3 metabolism, Interferon Regulatory Factor-7 metabolism, Interferon-Induced Helicase, IFIH1, Liver immunology, Luciferases, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microarray Analysis, Oligonucleotides genetics, Plasmodium genetics, Real-Time Polymerase Chain Reaction, Statistics, Nonparametric, Immunity, Innate immunology, Interferon Type I immunology, Liver parasitology, Plasmodium immunology, Signal Transduction immunology
- Abstract
Before they infect red blood cells and cause malaria, Plasmodium parasites undergo an obligate and clinically silent expansion phase in the liver that is supposedly undetected by the host. Here, we demonstrate the engagement of a type I interferon (IFN) response during Plasmodium replication in the liver. We identified Plasmodium RNA as a previously unrecognized pathogen-associated molecular pattern (PAMP) capable of activating a type I IFN response via the cytosolic pattern recognition receptor Mda5. This response, initiated by liver-resident cells through the adaptor molecule for cytosolic RNA sensors, Mavs, and the transcription factors Irf3 and Irf7, is propagated by hepatocytes in an interferon-α/β receptor-dependent manner. This signaling pathway is critical for immune cell-mediated host resistance to liver-stage Plasmodium infection, which we find can be primed with other PAMPs, including hepatitis C virus RNA. Together, our results show that the liver has sensor mechanisms for Plasmodium that mediate a functional antiparasite response driven by type I IFN.
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- 2014
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49. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.
- Author
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Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza Mdo C, Franklin BS, Elian S, Martins FS, Pereira D, Reed G, Fitzgerald KA, Golenbock DT, and Gazzinelli RT
- Subjects
- Animals, Bacterial Infections genetics, Bacterial Infections immunology, Carrier Proteins genetics, Carrier Proteins immunology, Caspase 1 genetics, Caspase 1 immunology, Female, Humans, Inflammasomes genetics, Inflammasomes immunology, Inflammasomes metabolism, Inflammation genetics, Inflammation immunology, Inflammation metabolism, Inflammation pathology, Interleukin-1beta genetics, Interleukin-1beta immunology, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins immunology, Malaria, Vivax immunology, Malaria, Vivax metabolism, Malaria, Vivax pathology, Male, Mice, Mice, Knockout, Monocytes immunology, Monocytes metabolism, Monocytes pathology, NLR Family, Pyrin Domain-Containing 3 Protein, Plasmodium chabaudi immunology, Plasmodium vivax immunology, Shock, Septic genetics, Shock, Septic immunology, Shock, Septic metabolism, Shock, Septic pathology, Bacterial Infections metabolism, Carrier Proteins metabolism, Caspase 1 metabolism, Intracellular Signaling Peptides and Proteins metabolism, Malaria, Vivax microbiology, Plasmodium chabaudi metabolism, Plasmodium vivax metabolism
- Abstract
Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1β. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-γ-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1β expression required a second stimulation with LPS and was also dependent on IFN-γ-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1β upon a second microbial stimulus, and became hypersensitive to septic shock. Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents. Similar to mice, we observed a significantly increased frequency of circulating CD14(+)CD16(-)Caspase-1(+) and CD14(dim)CD16(+)Caspase-1(+) monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1β after stimulation with LPS. Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes. We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1β and hypersensitivity to secondary bacterial infection during malaria.
- Published
- 2014
- Full Text
- View/download PDF
50. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.
- Author
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Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, and Moore KJ
- Subjects
- Animals, CD36 Antigens genetics, Carrier Proteins genetics, Inflammasomes immunology, Interleukin-1beta immunology, Lipoproteins, LDL immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Microscopy, Fluorescence, NLR Family, Pyrin Domain-Containing 3 Protein, RNA chemistry, RNA genetics, Real-Time Polymerase Chain Reaction, Alzheimer Disease immunology, Atherosclerosis immunology, CD36 Antigens immunology, Carrier Proteins immunology, Diabetes Mellitus, Type 2 immunology, Inflammation immunology
- Abstract
Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.
- Published
- 2013
- Full Text
- View/download PDF
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