18 results on '"Tengesdal IW"'
Search Results
2. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo
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Lorenzo Dagna, Richard A. Spritz, Ying Jin, Brent E. Palmer, Henry A. Erlich, Melinda Rastrou, Giulio Cavalli, Daniel Yorgov, Isak W. Tengesdal, Stephanie A. Santorico, Cherie Holcomb, Charles A. Dinarello, C. Preston Neff, Masahiro Hayashi, Cavalli, G, Hayashi, M, Jin, Y, Yorgov, D, Santorico, Sa, Holcomb, C, Rastrou, M, Erlich, H, Tengesdal, Iw, Dagna, Lorenzo, Neff, Cp, Palmer, Be, Spritz, Ra, and Dinarello, Ca
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0301 basic medicine ,Vitiligo ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Single-nucleotide polymorphism ,Major histocompatibility complex ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Autoimmune Diseases ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,HLA-DQ Antigens ,HLA-DQ ,HLA-DR ,medicine ,Humans ,MHC class II ,Multidisciplinary ,biology ,Haplotype ,Histocompatibility Antigens Class II ,HLA-DR Antigens ,Biological Sciences ,medicine.disease ,Enhancer Elements, Genetic ,030104 developmental biology ,Haplotypes ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Cytokines - Abstract
Item does not contain fulltext Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-gamma and IL-1beta than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-gamma on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1beta was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.
- Published
- 2016
3. Screening NLRP3 drug candidates in clinical development: lessons from existing and emerging technologies.
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Tengesdal IW, Banks M, Dinarello CA, and Marchetti C
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- Humans, Animals, Drug Evaluation, Preclinical, Interleukin-1beta metabolism, Interleukin-1beta antagonists & inhibitors, Inflammasomes metabolism, Signal Transduction drug effects, Inflammation drug therapy, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Drug Development methods
- Abstract
Decades of evidence positioned IL-1β as a master regulatory cytokine in acute and chronic inflammatory diseases. Approved biologics aimed at inhibiting IL-1 signaling have shown efficacy but variable safety. More recently, targeting NLRP3 activation, an upstream mediator of IL-1β, has garnered the most attention. Aberrant NLRP3 activation has been demonstrated to participate in the progression of several pathological conditions from neurogenerative diseases to cardio-metabolic syndromes and cancer. Pharmacological and genetic strategies aimed to limit NLRP3 function have proven effective in many preclinical models of diseases. These evidences have lead to a significant effort in the generation and clinical testing of small orally active molecules that can target NLRP3. In this report, we discuss different properties of these molecules with translational potential and describe the technologies currently available to screen NLRP3 targeting molecules highlighting advantages and limitations of each method., Competing Interests: IT serves as consultant for Olatec and receives compensation. CD serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation, and has equity in Olatec. CM serves as Director for Olatec’s Innovative Science Program and has equity in Olatec. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tengesdal, Banks, Dinarello and Marchetti.)
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- 2024
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4. International nomenclature guidelines for the IL-1 family of cytokines and receptors.
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Gaballa JM, Højen JF, De Graaf DM, Amo-Aparicio J, Marchetti C, Cavalli G, Dinarello A, Li S, Corbisiero MF, Tengesdal IW, Redzic JS, Azam T, Webber WS 3rd, Pankratz KA, May MJ, Cominelli F, Eisenmesser EZ, Kim S, Dinarello CA, and Boraschi D
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- Cytokines, Interleukin-1
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- 2024
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5. NLRP3 and cancer: Pathogenesis and therapeutic opportunities.
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Tengesdal IW, Dinarello CA, and Marchetti C
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- Animals, Inflammasomes, Inflammation drug therapy, Interleukin-1, Reactive Oxygen Species, Neoplasms drug therapy, NLR Family, Pyrin Domain-Containing 3 Protein physiology
- Abstract
More than a decade ago IL-1 blockade was suggested as an add-on therapy for the treatment of cancer. This proposal was based on the overall safety record of anti-IL-1 biologics and the anti-tumor properties of IL-1 blockade in animal models of cancer. Today, a new frontier in IL-1 activity regulation has developed with several orally active NLRP3 inhibitors currently in clinical trials, including cancer. Despite an increasing body of evidence suggesting a role of NLRP3 and IL-1-mediated inflammation driving cancer initiation, immunosuppression, growth, and metastasis, NLRP3 activation in cancer remains controversial. In this review, we discuss the recent advances in the understanding of NLRP3 activation in cancer. Further, we discuss the current opportunities for NLRP3 inhibition in cancer intervention with novel small molecules., Competing Interests: Declaration of Competing Interest I.W.T. serves as consultant for Olatec and receives compensation. C.A.D. serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation, and has equity in Olatec. C.M. serves as Director for Olatec’s Innovative Science Program and has equity in Olatec., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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6. Dexamethasone and OLT1177 Cooperate in the Reduction of Melanoma Growth by Inhibiting STAT3 Functions.
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Dinarello A, Mills TS, Tengesdal IW, Powers NE, Azam T, and Dinarello CA
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- Humans, Animals, Mice, Inflammasomes metabolism, Dexamethasone pharmacology, Dexamethasone therapeutic use, STAT3 Transcription Factor metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Melanoma drug therapy
- Abstract
The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1β and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with the glucocorticoid dexamethasone. At sacrifice, OLT1177 treated mice had significantly smaller tumors compared to tumor-bearing mice treated with vehicle. However, the combined treatment of OLT1177 plus dexamethasone revealed a greater suppression of tumor growth. This reduction was accompanied by a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription and by a significant reduction of STAT3 Y705 and S727 phosphorylations in the tumors. In vitro, the human melanoma cell line 1205Lu, stimulated with IL-1α, exhibited significantly lower levels of STAT3 Y705 phosphorylation by the combination treatment, thus affecting the nuclear functions of STAT3. In the same cells, STAT3 serine 727 phosphorylation was also lower, affecting the mitochondrial functions of STAT3. In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3.
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- 2023
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7. IL-38 Gene Deletion Worsens Murine Colitis.
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de Graaf DM, Wang RX, Amo-Aparicio J, Lee JS, Dowdell AS, Tengesdal IW, Marchetti C, Colgan SP, Joosten LAB, and Dinarello CA
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- Animals, Cytokines, Dextran Sulfate, Gene Deletion, Interleukin-1 genetics, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, RNA, Messenger, Weight Loss, Colitis chemically induced, Colitis genetics, Colitis metabolism, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases pathology, Interleukin-1 metabolism
- Abstract
IL-38 is a recently discovered cytokine and member of the IL-1 Family. In the IL-1 Family, IL-38 is unique because the cytokine is primarily a B lymphocyte product and functions to suppress inflammation. Studies in humans with inflammatory bowel disease (IBD) suggest that IL-38 may be protective for ulcerative colitis or Crohn's disease, and that IL-38 acts to maintain homeostasis in the intestinal tract. Here we investigated the role of endogenous IL-38 in experimental colitis in mice deficient in IL-38 by deletion of exons 1-4 in C57 BL/6 mice. Compared to WT mice, IL-38 deficient mice subjected to dextran sulfate sodium (DSS) showed greater severity of disease, more weight loss, increased intestinal permeability, and a worse histological phenotype including increased neutrophil influx in the colon. Mice lacking IL-38 exhibited elevated colonic Nlrp3 mRNA and protein levels, increased caspase-1 activation, and the concomitant increased processing of IL-1β precursor into active IL-1β. Expression of IL-1α, an exacerbator of IBD, was also upregulated. Colonic myleloperoxidase protein and Il17a , and Il17f mRNA levels were higher in the IL-38 deficient mice. Daily treatment of IL-38 deficient mice with an NLRP3 inhibitor attenuated diarrhea and weight loss during the recovery phase. These data implicate endogenous IL-38 as an anti-inflammatory cytokine that reduces DSS colitis severity. We propose that a relative deficiency of IL-38 contributes to IBD by disinhibition of the NLRP3 inflammasome., Competing Interests: LJ serves on Olatec’s scientific advisory board and receives compensation. CD serves as chairman of Olatec’s scientific advisory board, is co-chief scientific officer, receives compensation, and has equity in Olatec. CM serves as director for Olatec’s innovative science program and has equity in Olatec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Graaf, Wang, Amo-Aparicio, Lee, Dowdell, Tengesdal, Marchetti, Colgan, Joosten and Dinarello.)
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- 2022
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8. Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers.
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Tengesdal IW, Li S, Powers NE, May M, Neff CP, Joosten LAB, Marchetti C, and Dinarello CA
- Abstract
Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate the role of the host nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome in metastatic breast cancer. In vitro, we show that stimulation of THP-1 cells with conditioned media collected from MDA-MB-468 cells induced NLRP3 activation and increased Pdcd1l1 expression. In vivo, mice deficient in NLRP3 orthotopically implanted with metastatic breast cancer cell line (E0771) showed significant reduction in tumor growth (p < 0.05) and increased survival (p < 0.01). Inhibition of NLRP3 with the small molecule OLT1177® reduced expression of Pdcd1l1 (p < 0.001), Casp1 (p < 0.01) and Il1b (p < 0.01) in primary tumors. Furthermore, tumor-bearing mice receiving OLT1177® showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) (p < 0.001) and increased CD8+ T cells (p < 0.05) and NK cells (p < 0.05) in the TME. NLRP3 inhibition in addition to anti-PD-1 treatment significantly reduced tumor growth from the monotherapies (p < 0.05). These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers.
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- 2022
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9. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.
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Molteni R, Biavasco R, Stefanoni D, Nemkov T, Domínguez-Andrés J, Arts RJ, Merelli I, Mazza D, Zambrano S, Panigada M, Cantoni E, Tengesdal IW, Maksud P, Piras F, Cesana D, Cassina L, Distefano G, Loffreda A, Gnani D, De Luca G, Tomelleri A, Campochiaro C, Joosten LAB, Dinarello CA, Kajaste-Rudnitski A, Haroche J, Cardaci S, Cenci S, Dagna L, Doglioni C, Ferrarini M, Ferrero E, Boletta A, D'Alessandro A, Montini E, Netea MG, and Cavalli G
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- Cells, Cultured, Epigenesis, Genetic, Erdheim-Chester Disease immunology, Erdheim-Chester Disease pathology, Humans, Immunity, Inflammation immunology, Inflammation pathology, Macrophages immunology, Macrophages metabolism, Macrophages pathology, Oncogenes, Point Mutation, Proto-Oncogene Proteins B-raf immunology, Erdheim-Chester Disease genetics, Inflammation genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation., (© 2021 by The American Society of Hematology.)
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- 2021
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10. Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression.
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Tengesdal IW, Dinarello A, Powers NE, Burchill MA, Joosten LAB, Marchetti C, and Dinarello CA
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- Animals, Cell Line, Tumor, Humans, Immune Tolerance drug effects, Immune Tolerance immunology, Interleukin-1beta metabolism, Interleukin-6 metabolism, Melanoma metabolism, Melanoma pathology, Melanoma, Experimental drug therapy, Melanoma, Experimental immunology, Melanoma, Experimental metabolism, Mice, Inbred C57BL, Mice, Knockout, Models, Immunological, Myeloid-Derived Suppressor Cells metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nitriles pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Signal Transduction immunology, Tumor Burden drug effects, Tumor Burden immunology, Mice, Interleukin-1beta immunology, Interleukin-6 immunology, Melanoma immunology, Myeloid-Derived Suppressor Cells immunology, NLR Family, Pyrin Domain-Containing 3 Protein immunology, STAT3 Transcription Factor immunology
- Abstract
Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL-6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor. In vivo , using B16F10 melanoma, OLT1177 effectively reduced tumor progression ( p < 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% ( p <0.01) and II6 expression by 53% ( p <0.05). Disruption of tumor-derived NLRP3, either pharmacologically or genetically, reduced STAT3 signaling in bone marrow cells. In PMN-MDSCs isolated from tumor-bearing mice treated with OLT1177, we observed significant reductions in immunosuppressive genes such as Pdcd1l1 , Arg1 , Il10 and Tgfb1 . In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1β induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs., Competing Interests: LJ serves on Olatec’s Scientific Advisory Board and receives compensation. CD serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation and has equity in Olatec. CM serves as Director for Olatec’s Innovative Science Program and has equity in Olatec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tengesdal, Dinarello, Powers, Burchill, Joosten, Marchetti and Dinarello.)
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- 2021
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11. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity.
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Cavalli G, Tengesdal IW, Gresnigt M, Nemkov T, Arts RJW, Domínguez-Andrés J, Molteni R, Stefanoni D, Cantoni E, Cassina L, Giugliano S, Schraa K, Mills TS, Pietras EM, Eisenmensser EZ, Dagna L, Boletta A, D'Alessandro A, Joosten LAB, Netea MG, and Dinarello CA
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- Animals, Candidiasis genetics, Candidiasis immunology, Candidiasis microbiology, Epigenesis, Genetic drug effects, Glycolysis drug effects, Glycolysis genetics, Host-Pathogen Interactions drug effects, Host-Pathogen Interactions immunology, Humans, Male, Mice, Inbred C57BL, Neutrophils drug effects, Neutrophils metabolism, Mice, Anti-Inflammatory Agents pharmacology, Immunity, Innate drug effects, Interleukin-1 pharmacology
- Abstract
Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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12. Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.
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Tengesdal IW, Menon DR, Osborne DG, Neff CP, Powers NE, Gamboni F, Mauro AG, D'Alessandro A, Stefanoni D, Henen MA, Mills TS, De Graaf DM, Azam T, Vogeli B, Palmer BE, Pietras EM, DeGregori J, Tan AC, Joosten LAB, Fujita M, Dinarello CA, and Marchetti C
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- Animals, CD8-Positive T-Lymphocytes immunology, Humans, Interleukin-1beta genetics, Interleukin-1beta immunology, Melanoma, Experimental genetics, Melanoma, Experimental pathology, Mice, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Neoplasm Proteins genetics, Signal Transduction genetics, Signal Transduction immunology, T-Lymphocytes, Regulatory immunology, Melanoma, Experimental immunology, Myeloid-Derived Suppressor Cells immunology, NLR Family, Pyrin Domain-Containing 3 Protein immunology, Neoplasm Proteins immunology
- Abstract
Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples ( n = 469) compared to normal skin ( n = 324), with a highly significant correlation between NLRP3 and IL-1β ( P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8
+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy., Competing Interests: Competing interest statement: L.A.B.J. serves on Olatec’s Scientific Advisory Board and receives compensation. C.A.D. serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation, and has equity in Olatec. C.M. serves as Director for Olatec’s Innovative Science Program and has equity in Olatec., (Copyright © 2021 the Author(s). Published by PNAS.)- Published
- 2021
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13. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.
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Klück V, Jansen TLTA, Janssen M, Comarniceanu A, Efdé M, Tengesdal IW, Schraa K, Cleophas MCP, Scribner CL, Skouras DB, Marchetti C, Dinarello CA, and Joosten LAB
- Abstract
Background: Gout flares are driven by interleukin (IL)-1β. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1β. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare., Methods: In this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18-80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed., Findings: Between May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving <80% of study drug and two had major protocol deviations): eight patients received 100 mg/day, seven received 300 mg/day, six received 1000 mg/day, and eight received 2000 mg/day. Between baseline and day 3, there was a mean reduction in patient-reported target joint pain of 52·4% (SD 32·94; p=0∙016) for the 100 mg/day group, 68·4% (34·29; p=0∙016) for the 300 mg/day group, 55·8% (44·90; p=0∙063) for the 1000 mg/day group, and 57·6% (38·72; p=0∙016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82·1% (22·68; p=0∙031) for the 100 mg/day group, 84·2% (16·33; p=0∙016) for the 300 mg/day group, 68·9% (34·89; p=0∙031) for the 1000 mg/day group, and 83·9% (15·44; p=0∙008) for the 2000 mg/day group, compared to baseline. 25 (73·5%) of 34 patients reported a total of 45 treatment-emergent adverse events, most of which were metabolism and nutrition disorders (17 [37·8%]) and gastrointestinal disorders (ten [22·2%]). Two serious adverse events occurred during the study, admission to hospital because of worsening of gout flare at day 3, and admission to hospital because of coronary stenosis 18 days after the patient received their last dose; these were considered moderate in severity and unrelated to the study drug., Interpretation: Dapansutrile is a specific NLRP3 inflammasome inhibitor with a satisfactory safety profile and efficacy in the reduction of target joint pain in this study. Future studies are needed to confirm the clinical potential of dapansutrile.
- Published
- 2020
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14. Role for nuclear interleukin-37 in the suppression of innate immunity.
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Li S, Amo-Aparicio J, Neff CP, Tengesdal IW, Azam T, Palmer BE, López-Vales R, Bufler P, and Dinarello CA
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- Animals, Cell Nucleus metabolism, Cytokines metabolism, Female, Interleukin-1 genetics, Lipopolysaccharides pharmacology, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, NF-kappa B metabolism, Protein Transport, Immunity, Innate genetics, Interleukin-1 physiology
- Abstract
The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1β, IL-6, TNFα and IFNγ by 40-50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1β, IL-6, and TNFα in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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15. The selective ROCK2 inhibitor KD025 reduces IL-17 secretion in human peripheral blood mononuclear cells independent of IL-1 and IL-6.
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Tengesdal IW, Kitzenberg D, Li S, Nyuydzefe MS, Chen W, Weiss JM, Zhang J, Waksal SD, Zanin-Zhorov A, and Dinarello CA
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- Candida albicans, Cells, Cultured, Humans, Interleukin-1beta immunology, Lectins, C-Type agonists, Leukocytes, Mononuclear drug effects, Phosphorylation, STAT3 Transcription Factor, Signal Transduction, Staphylococcus epidermidis, Heterocyclic Compounds, 4 or More Rings pharmacology, Interleukin-17 immunology, Interleukin-1alpha immunology, Interleukin-6 immunology, Leukocytes, Mononuclear immunology, rho-Associated Kinases antagonists & inhibitors
- Abstract
Reducing the activities of the pro-inflammatory cytokine IL-17 is an effective treatment strategy for several chronic autoimmune disorders. Rho-associated coiled-coil containing kinase 2 (ROCK2) is a member of the serine-threonine protein kinase family that regulates IL-17 secretion in T cells via signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. We reported here that the selective ROCK2 inhibitor KD025 significantly reduced in vitro production of IL-17 in unfractionated human peripheral blood mononuclear cells (PBMCs) stimulated with the dectin-1 agonist Candida albicans. C. albicans induced IL-17 was reduced by 70% (p < 0.0001); a similar reduction (80%) was observed in PBMC stimulated with the Toll-like receptor 2 agonist Staphylococcus epidermidis (p < 0.0001). Treatment of PBMC with KD025 was not associated with a reduction in IL-1β, IL-6 or IL-1α levels; in contrast, a 1.5 fold increase in the level of IL-1 receptor antagonist (IL-1Ra) was observed (p < 0.001). KD025 down-regulated C. albicans-induced Myosin Light Chain and STAT3, whereas STAT5 phosphorylation increased. Using anti-CD3/CD28 activation of the TCR, KD025 similarly suppressed IL-17 independent of a reduction in IL-1β. Thus, ROCK2 directly regulates IL-17 secretion independent of endogenous IL-1 and IL-6 supporting development of selective ROCK2 inhibitors for treatment of IL-17-driven inflammatory diseases., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
- Full Text
- View/download PDF
16. Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue.
- Author
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Ballak DB, Li S, Cavalli G, Stahl JL, Tengesdal IW, van Diepen JA, Klück V, Swartzwelter B, Azam T, Tack CJ, Stienstra R, Mandrup-Poulsen T, Seals DR, and Dinarello CA
- Subjects
- Animals, Biomarkers blood, Diet, High-Fat, Glucose Tolerance Test, Humans, Interleukin-1 genetics, Metabolic Syndrome metabolism, Metabolic Syndrome physiopathology, Mice, Mice, Transgenic, Receptors, Interleukin-1 Type I antagonists & inhibitors, Recombinant Proteins genetics, Recombinant Proteins therapeutic use, Adipose Tissue metabolism, Cytokines biosynthesis, Inflammation Mediators metabolism, Insulin Resistance, Interleukin-1 therapeutic use, Metabolic Syndrome drug therapy, Obesity physiopathology
- Abstract
Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 μg/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and C X C motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1α in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pm IL-37 reduced spontaneous release of TNFα and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity., (© 2018 Ballak et al.)
- Published
- 2018
- Full Text
- View/download PDF
17. NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis.
- Author
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Marchetti C, Swartzwelter B, Koenders MI, Azam T, Tengesdal IW, Powers N, de Graaf DM, Dinarello CA, and Joosten LAB
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Anti-Inflammatory Agents pharmacology, Arthritis, Experimental pathology, Arthritis, Gouty pathology, Arthritis, Reactive pathology, Inflammasomes antagonists & inhibitors, Nitriles pharmacology
- Abstract
Background: Activation of the NLRP3 inflammasome in gout amplifies the inflammatory response and mediates further damage. In the current study, we assessed the therapeutic effect of OLT1177, an orally active NLRP3 inflammasome inhibitor that is safe in humans, in murine acute arthritis models., Methods: Zymosan or monosodium urate (MSU) crystals were injected intra-articularly (i.a.) into mouse knee joints to induce reactive or gouty arthritis. Joint swelling, articular cell infiltration, and synovial cytokines were evaluated 25 hours and 4 hours following zymosan or MSU challenge, respectively. OLT1177 was administrated intraperitoneally by oral gavage or in the food by an OLT1177-enriched diet., Results: OLT1177 reduced zymosan-induced joint swelling (p < 0.001), cell influx (p < 0.01), and synovial levels of interleukin (IL)-1β, IL-6, and chemokine (C-X-C motif) ligand 1 (CXCL1) (p < 0.05), respectively, when compared with vehicle-treated mice. Plasma OLT1177 levels correlated (p < 0.001) dose-dependently with reduction in joint inflammation. Treatment of mice with OLT1177 limited MSU crystal articular inflammation (p > 0.0001), which was associated with decreased synovial IL-1β, IL-6, myeloperoxidase, and CXCL1 levels (p < 0.01) compared with vehicle-treated mice. When administrated orally 1 hour after MSU challenge, OLT1177 reduced joint inflammation, processing of IL-1β, and synovial phosphorylated c-Jun N-terminal kinase compared with the vehicle group. Mice were fed an OLT1177-enriched diet for 3 weeks and then challenged i.a. with MSU crystals. Joint swelling, synovial IL-1β, and expression of Nlrp3 and Il1b were significantly reduced in synovial tissues in mice fed an OLT1177-enriched diet when compared with the standard diet group., Conclusions: Oral OLT1177 is highly effective in ameliorating reactive as well as gouty arthritis.
- Published
- 2018
- Full Text
- View/download PDF
18. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo.
- Author
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Cavalli G, Hayashi M, Jin Y, Yorgov D, Santorico SA, Holcomb C, Rastrou M, Erlich H, Tengesdal IW, Dagna L, Neff CP, Palmer BE, Spritz RA, and Dinarello CA
- Subjects
- Enhancer Elements, Genetic, Haplotypes, Humans, Polymorphism, Single Nucleotide, Autoimmune Diseases immunology, Cytokines biosynthesis, HLA-DQ Antigens immunology, HLA-DR Antigens immunology, Histocompatibility Antigens Class II immunology, Vitiligo immunology
- Abstract
Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.
- Published
- 2016
- Full Text
- View/download PDF
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