249 results on '"Kanneganti A"'
Search Results
2. Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging
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Luo, Hanzhi, Mu, Wei-Chieh, Karki, Rajendra, Chiang, Hou-Hsien, Mohrin, Mary, Shin, Jiyung J, Ohkubo, Rika, Ito, Keisuke, Kanneganti, Thirumala-Devi, and Chen, Danica
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Biochemistry and Cell Biology ,Biological Sciences ,Aging ,Regenerative Medicine ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Inflammatory and immune system ,Animals ,Cellular Senescence ,Hematopoietic Stem Cells ,Inflammasomes ,Mice ,Mice ,Knockout ,Mitochondria ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Sirtuin 2 ,Stress ,Physiological ,NLRP3 ,SIRT2 ,SIRT3 ,SIRT7 ,aging ,clonal hematopoiesis ,hematopoietic stem cell ,inflammasome ,mitochondrial UPR ,oxidative stress ,Medical Physiology ,Biological sciences - Abstract
Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the NLRP3 inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the NLRP3 inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that SIRT2, a cytosolic NAD+-dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the NLRP3 inflammasome in HSCs cell autonomously. With age, reduced SIRT2 expression and increased mitochondrial stress lead to aberrant activation of the NLRP3 inflammasome in HSCs. SIRT2 overexpression, NLRP3 inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging.
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- 2019
3. Chromatin Regulator SMARCA4 Is Essential for MHV-Induced Inflammatory Cell Death, PANoptosis.
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Malireddi, R. K. Subbarao and Kanneganti, Thirumala-Devi
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CELL death , *VIRUS diseases , *HEPATITIS A virus , *VIRAL hepatitis , *HEPATITIS viruses - Abstract
The innate immune system serves as the first line of defense against β-coronaviruses (β-CoVs), a family of viruses that includes SARS-CoV-2. Viral sensing via pattern recognition receptors triggers inflammation and cell death, which are essential components of the innate immune response that facilitate viral clearance. However, excessive activation of the innate immune system and inflammatory cell death can result in uncontrolled release of proinflammatory cytokines, resulting in cytokine storm and pathology. PANoptosis, innate immune, inflammatory cell death initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes, has been implicated in the pathology of viral infections. Therefore, understanding the molecular mechanisms regulating PANoptosis in response to β-CoV infection is critical for identifying new therapeutic targets that can mitigate disease severity. In the current study, we analyzed findings from a cell death-based CRISPR screen with archetypal β-CoV mouse hepatitis virus (MHV) as the trigger to characterize host molecules required for inflammatory cell death. As a result, we identified SMARCA4, a chromatin regulator, as a putative host factor required for PANoptosis in response to MHV. Furthermore, we observed that gRNA-mediated deletion of Smarca4 inhibited MHV-induced PANoptotic cell death in macrophages. These findings have potential translational and clinical implications for the advancement of treatment strategies for β-CoVs and other infections. [ABSTRACT FROM AUTHOR]
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- 2024
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4. ZBP1 Drives IAV-Induced NLRP3 Inflammasome Activation and Lytic Cell Death, PANoptosis, Independent of the Necroptosis Executioner MLKL
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R. K. Subbarao Malireddi, Bhesh Raj Sharma, Ratnakar R. Bynigeri, Yaqiu Wang, Jianlin Lu, and Thirumala-Devi Kanneganti
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IAV ,cell death ,PANoptosis ,necroptosis ,inflammasome ,MLKL ,Microbiology ,QR1-502 - Abstract
Influenza A virus (IAV) continues to pose a significant global health threat, causing severe respiratory infections that result in substantial annual morbidity and mortality. Recent research highlights the pivotal role of innate immunity, cell death, and inflammation in exacerbating the severity of respiratory viral diseases. One key molecule in this process is ZBP1, a well-recognized innate immune sensor for IAV infection. Upon activation, ZBP1 triggers the formation of a PANoptosome complex containing ASC, caspase-8, and RIPK3, among other molecules, leading to inflammatory cell death, PANoptosis, and NLRP3 inflammasome activation for the maturation of IL-1β and IL-18. However, the role for other molecules in this process requires further evaluation. In this study, we investigated the role of MLKL in regulating IAV-induced cell death and NLRP3 inflammasome activation. Our data indicate IAV induced inflammatory cell death through the ZBP1-PANoptosome, where caspases and RIPKs serve as core components. However, IAV-induced lytic cell death was only partially dependent on RIPK3 at later timepoints and was fully independent of MLKL throughout all timepoints tested. Additionally, NLRP3 inflammasome activation was unaffected in MLKL-deficient cells, establishing that MLKL and MLKL-dependent necroptosis do not act upstream of NLRP3 inflammasome activation, IL-1β maturation, and lytic cell death during IAV infection.
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- 2023
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5. Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression
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R.K. Subbarao Malireddi, Ratnakar R. Bynigeri, Balabhaskararao Kancharana, Bhesh Raj Sharma, Amanda R. Burton, Stephane Pelletier, and Thirumala-Devi Kanneganti
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PAMP ,innate immunity ,inflammation ,inflammasome ,IL-1α ,IL-1β ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Interleukin 1α (IL-1α) and IL-1β are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse (Il1a-KOline1), showing reduced IL-1β expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice (Il1a-KOline2) using CRISPR-Cas9 technology. In contrast to cells from Il1a-KOline1, where IL-1β expression was drastically reduced, bone marrow-derived macrophages (BMDMs) from Il1a-KOline2 mice showed normal induction and activation of IL-1β. Additionally, Il1a-KOline2 BMDMs showed normal inflammasome activation and IL-1β expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, using Il1a-KOline2 cells, we confirmed that IL-1α, independent of IL-1β, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1β. Future studies on the unique functions of IL-1α and IL-1β using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies.
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- 2022
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6. Single cell analysis of PANoptosome cell death complexes through an expansion microscopy method
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Wang, Yaqiu, Pandian, Nagakannan, Han, Joo-Hui, Sundaram, Balamurugan, Lee, SangJoon, Karki, Rajendra, Guy, Clifford S., and Kanneganti, Thirumala-Devi
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- 2022
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7. Fungal cell wall components modulate our immune system
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Benoit Briard, Thierry Fontaine, Thirumala-Devi Kanneganti, Neil A.R. Gow, and Nicolas Papon
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Innate immunity ,Trained immunity ,Inflammasome ,Cell death ,Pyroptosis ,PANoptosis ,Cytology ,QH573-671 - Abstract
Invasive fungal infections remain highly problematic for human health. Collectively, they account for more than 1 million deaths a year in addition to more than 100 million mucosal infections and 1 billion skin infections. To be able to make progress it is important to understand the pathobiology of fungal interactions with the immune system. Here, we highlight new advancements pointing out the pivotal role of fungal cell wall components (β-glucan, mannan, galactosaminogalactan and melanin) in modulating host immunity and discuss how these open new opportunities for the development of immunomodulatory strategies to combat deadly fungal infectious diseases.
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- 2021
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8. Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19.
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Malireddi, R.K. Subbarao, Sharma, Bhesh Raj, and Kanneganti, Thirumala-Devi
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The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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9. ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis)
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R. K. Subbarao Malireddi, Sannula Kesavardhana, and Thirumala-Devi Kanneganti
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caspase-1 ,gasdermin D ,MLKL ,inflammasome ,infection ,innate immunity ,Microbiology ,QR1-502 - Abstract
Cell death is central to development, organismal homeostasis, and immune responses. The cell death field has experienced tremendous progress by delineating the molecular programs specific to each of the apoptotic and inflammatory cell death pathways. Moreover, the discovery of the inflammasomes and pyroptosis and necroptosis pathway regulators have provided the genetic basis for the programmed inflammatory cell death pathways. Earlier research highlighted the unique regulation of each of these pathways, but emerging studies discovered co-regulation and crosstalk between these seemingly different cell death complexes. The progress in this area has led to an idea that master regulators play central roles in orchestrating multiple cell death pathways. Here, we provide a brief review of the master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3–FADD–caspase-8 cell death complex assembly and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis, which we dubbed here as PAN-optosis. Furthermore, we discuss the implications and therapeutic potential of targeting these master regulators in health and disease.One Sentence SummaryZBP1 and TAK1 regulate PAN-optosis.
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- 2019
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10. ZBP1 Drives IAV-Induced NLRP3 Inflammasome Activation and Lytic Cell Death, PANoptosis, Independent of the Necroptosis Executioner MLKL.
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Malireddi, R. K. Subbarao, Sharma, Bhesh Raj, Bynigeri, Ratnakar R., Wang, Yaqiu, Lu, Jianlin, and Kanneganti, Thirumala-Devi
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CELL death ,NLRP3 protein ,INFLAMMASOMES ,EXECUTIONS & executioners ,NATURAL immunity - Abstract
Influenza A virus (IAV) continues to pose a significant global health threat, causing severe respiratory infections that result in substantial annual morbidity and mortality. Recent research highlights the pivotal role of innate immunity, cell death, and inflammation in exacerbating the severity of respiratory viral diseases. One key molecule in this process is ZBP1, a well-recognized innate immune sensor for IAV infection. Upon activation, ZBP1 triggers the formation of a PANoptosome complex containing ASC, caspase-8, and RIPK3, among other molecules, leading to inflammatory cell death, PANoptosis, and NLRP3 inflammasome activation for the maturation of IL-1β and IL-18. However, the role for other molecules in this process requires further evaluation. In this study, we investigated the role of MLKL in regulating IAV-induced cell death and NLRP3 inflammasome activation. Our data indicate IAV induced inflammatory cell death through the ZBP1-PANoptosome, where caspases and RIPKs serve as core components. However, IAV-induced lytic cell death was only partially dependent on RIPK3 at later timepoints and was fully independent of MLKL throughout all timepoints tested. Additionally, NLRP3 inflammasome activation was unaffected in MLKL-deficient cells, establishing that MLKL and MLKL-dependent necroptosis do not act upstream of NLRP3 inflammasome activation, IL-1β maturation, and lytic cell death during IAV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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11. Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease.
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Chen, Wen, Gullett, Jessica M., Tweedell, Rebecca E., and Kanneganti, Thirumala‐Devi
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CELL death ,PYROPTOSIS ,APOPTOSIS ,DRUG target - Abstract
Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including nonlytic and lytic pathways. Apoptosis is the most well‐characterized nonlytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of cross‐talk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen‐associated molecular patterns (PAMPs), damage‐associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors and regulators, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]
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- 2023
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12. The NLRC4 inflammasome requires IRF8-dependent production of NAIPs
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Ein Lee, Rajendra Karki, and Thirumala-Devi Kanneganti
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IRF8 ,NLRC4 ,Inflammasome ,NAIPs ,Salmonella ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Activation of the NLRC4 inflammasome is crucial for defense against bacterial species that have flagellin or the type III secretion system (T3SS). We have discovered the role of interferon regulatory factor 8 (IRF8) in mediating NLRC4 inflammasome activation. IRF8 is required for the transcription of genes encoding NAIPs, thereby enabling cellular detection of flagellin or T3SS proteins. In vivo, IRF8 is important for NLRC4 inflammasome–dependent cytokine production, bacterial clearance, and ultimately, host survival. By introducing IRF8 as a player in inflammasome regulation, our study provides a new perspective on that process.
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- 2018
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13. NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis
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Gurung, Prajwal, Burton, Amanda, and Kanneganti, Thirumala-Devi
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- 2016
14. Advances in Understanding Activation and Function of the NLRC4 Inflammasome
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Balamurugan Sundaram and Thirumala-Devi Kanneganti
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NOD-like receptors ,NLR ,NLRC4 ,NAIP ,IRF8 ,inflammasome ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1–mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro–IL-1β and pro–IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Salmonella Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease.
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- 2021
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15. NLRP12‐PANoptosome in haemolytic, infectious and inflammatory diseases.
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Tweedell, Rebecca E. and Kanneganti, Thirumala‐Devi
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COMMUNICABLE diseases - Abstract
Keywords: caspase; inflammasome; inflammatory cell death; IRF1; NLRP3; PANoptosis; RIPK3; TLR2; TLR4 EN caspase inflammasome inflammatory cell death IRF1 NLRP3 PANoptosis RIPK3 TLR2 TLR4 1 4 4 10/03/23 20230901 NES 230901 Invading pathogens and homeostatic perturbations activate the innate immune system as the body's first line of defense. After the two-decades-long search for the trigger of NLRP12, this study not only identified the trigger but also NLRP12's novel role in inducing a unique inflammatory cell death pathway, PANoptosis. Indeed, the NLRP12-PANoptosome was regulated through NLRP12 expression, suggesting that NLRP12 is not directly binding to heme or PAMPs for sensing but is instead sensing the associated homeostatic perturbations. [Extracted from the article]
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- 2023
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16. Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
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Hongbo Yu, Fei Liu, Hiroto Kambara, Xuemei Xie, Maikel Acosta-Zaldívar, Cunling Zhang, Julia R. Köhler, Jiajia Li, Hongbo R. Luo, Rongxia Guo, Ning-Ning Liu, Ting Bei, Fengxia Ma, Li Zhao, Xionghui Ding, Wenli Han, Xiaoyu Zhang, Wanjun Qi, and Apurva Kanneganti
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Programmed cell death ,Inflammasomes ,Science ,Interleukin-1beta ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Kidney ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Sepsis ,Mediator ,Candida albicans ,medicine ,Animals ,Humans ,Cells, Cultured ,Mice, Knockout ,Multidisciplinary ,biology ,Immune cell death ,Macrophages ,Caspase 1 ,Candidiasis ,Intracellular Signaling Peptides and Proteins ,Pyroptosis ,Inflammasome ,General Chemistry ,Phosphate-Binding Proteins ,medicine.disease ,biology.organism_classification ,Corpus albicans ,Mice, Inbred C57BL ,Host-Pathogen Interactions ,Female ,Infection ,Candidalysin ,medicine.drug - Abstract
Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis., Inflammasome signalling has been shown to protect Candida albicans during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in C.ablicans immune evasion and suggests its targeting therapeutically.
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- 2021
17. Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5
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Matusiak, Magdalena, Van Opdenbosch, Nina, Walle, Lieselotte Vande, Sirard, Jean-Claude, Kanneganti, Thirumala-Devi, and Lamkanfi, Mohamed
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- 2015
18. AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence
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Ravi C. Kalathur, SangJoon Lee, Thirumala-Devi Kanneganti, Lam Nhat Nguyen, Rajendra Karki, and Yaqiu Wang
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Male ,Damp ,THP-1 Cells ,Apoptosis ,Herpesvirus 1, Human ,medicine.disease_cause ,Pyrin domain ,Mice ,RIPK1 ,AIM2 ,Pyroptosis ,medicine ,Animals ,Humans ,FADD ,Francisella novicida ,Francisella ,Cells, Cultured ,Multidisciplinary ,Innate immune system ,biology ,Caspase 1 ,RNA-Binding Proteins ,Inflammasome ,Pyrin ,Cell biology ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Necroptosis ,biology.protein ,Cytokines ,Female ,medicine.drug - Abstract
Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells1. There are several inflammasome sensors that each detect and respond to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively)1. During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors2–5. Here we found that AIM2 regulates the innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex virus 1 and Francisella novicida. We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding of the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases. AIM2 responds to infection with herpes simplex virus 1 or Francisella novicida by driving assembly of a large multi-protein complex containing multiple inflammasome sensors and cell death regulators.
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- 2021
19. From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways
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Yaqiu Wang and Thirumala-Devi Kanneganti
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Cell death ,Programmed cell death ,Necroptosis ,Biophysics ,Caspase 1 ,Apoptosis ,Review ,Biology ,Caspase 8 ,RIPK3 ,ASC ,Biochemistry ,Caspase 7 ,Inflammasome ,NLRP3 ,Structural Biology ,Genetics ,medicine ,Pyroptosis ,PANoptosis ,ComputingMethodologies_COMPUTERGRAPHICS ,ZBP1 ,PANoptosome ,Gasdermin E ,Computer Science Applications ,Gasdermin D ,Crosstalk (biology) ,Caspase-3 ,Caspase-1 ,Caspase-8 ,Neuroscience ,TP248.13-248.65 ,medicine.drug ,Biotechnology ,Caspase-7 ,MLKL - Abstract
Graphical abstract, Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.
- Published
- 2021
20. Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors
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Gurung, Prajwal and Kanneganti, Thirumala-Devi
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- 2016
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21. RIPK3 Promotes Mefv Expression and Pyrin Inflammasome Activation via Modulation of mTOR Signaling
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Arjun Balakrishnan, Thirumala-Devi Kanneganti, Ankit Malik, R. K. Subbarao Malireddi, and Deepika Sharma
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biology ,Chemistry ,Necroptosis ,Immunology ,Familial Mediterranean fever ,Inflammasome ,medicine.disease ,MEFV ,Pyrin domain ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,biology.protein ,Immunology and Allergy ,Inflammasome complex ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,030215 immunology ,medicine.drug - Abstract
Mutations in MEFV, the gene encoding pyrin in humans, are associated with the autoinflammatory disorder familial Mediterranean fever. Pyrin is an innate sensor that assembles into an inflammasome complex in response to Rho-modifying toxins, including Clostridium difficile toxins A and B. Cell death pathways have been shown to intersect with and modulate inflammasome activation, thereby affecting host defense. Using bone marrow–derived macrophages and a murine model of peritonitis, we show in this study that receptor-interacting protein kinase (RIPK) 3 impacts pyrin inflammasome activation independent of its role in necroptosis. RIPK3 was instead required for transcriptional upregulation of Mefv through negative control of the mechanistic target of rapamycin (mTOR) pathway and independent of alterations in MAPK and NF-κB signaling. RIPK3 did not affect pyrin dephosphorylation associated with inflammasome activation. We further demonstrate that inhibition of mTOR was sufficient to promote Mefv expression and pyrin inflammasome activation, highlighting the cross-talk between the mTOR pathway and regulation of the pyrin inflammasome. Our study reveals a novel interaction between molecules involved in cell death and the mTOR pathway to regulate the pyrin inflammasome, which can be harnessed for therapeutic interventions.
- Published
- 2020
22. ADAR1 and ZBP1 in innate immunity, cell death, and disease.
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Karki, Rajendra and Kanneganti, Thirumala-Devi
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CELL death , *NATURAL immunity , *IMMUNOREGULATION , *SYSTEMIC lupus erythematosus , *RNA editing - Abstract
ADAR1 and ZBP1 are mammalian interferon-inducible proteins containing Zα domains that regulate innate immune responses across development and disease. Mutations in ADAR1 are associated with several autoimmune and autoinflammatory disorders in humans, such as Aicardi-Goutières Syndrome 6, systemic lupus erythematosus, and bilateral striatal necrosis. There is a regulatory relationship between ADAR1 and ZBP1 in mammalian cells, where ADAR1 suppresses ZBP1-mediated inflammatory cell death, PANoptosis. ZBP1-mediated PANoptosis contributes to the pathology caused by impaired ADAR1 function in mice. Using nuclear export inhibitors to sequester ADAR1 in the nucleus and disrupt the cytoplasmic interaction between ADAR1 and ZBP1, and activating ZBP1 through the induction of dsRNA have shown promise in preclinical mouse models. ADAR1 and ZBP1 are the only two mammalian Zα-containing proteins; they regulate innate immune responses crucial for survival, development, and host defense against infection, inflammatory diseases, and cancers. While the interaction of ADAR1 with ZBP1 suppresses cell death, the interaction of RIPK3 with ZBP1 drives innate immune inflammatory cell death (i.e., PANoptosis). Molecules that can modulate the ADAR1-ZBP1 or RIPK3-ZBP1 interaction have therapeutic potential for the treatment of inflammatory and infectious diseases. ADAR1 and ZBP1 are the only two mammalian proteins that contain Zα domains, which are thought to bind to nucleic acids in the Z-conformation. These two molecules are crucial in regulating diverse biological processes. While ADAR1-mediated RNA editing supports host survival and development, ZBP1-mediated immune responses provide host defense against infection and disease. Recent studies have expanded our understanding of the functions of ADAR1 and ZBP1 beyond their classical roles and established their fundamental regulation of innate immune responses, including NLRP3 inflammasome activation, inflammation, and cell death. Their roles in these processes have physiological impacts across development, infectious and inflammatory diseases, and cancer. In this review, we discuss the functions of ADAR1 and ZBP1 in regulating innate immune responses in development and disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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23. Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection
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R. K. Subbarao Malireddi, Rudragouda Channappanavar, Richard J. Webby, Evan P. Williams, Rajendra Karki, Balaji Banoth, Thirumala-Devi Kanneganti, Amanda R. Burton, Min Zheng, and Colleen B. Jonsson
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0301 basic medicine ,Programmed cell death ,030102 biochemistry & molecular biology ,viruses ,Necroptosis ,Pyroptosis ,Caspase 1 ,Inflammasome ,Cell Biology ,Biology ,medicine.disease_cause ,Caspase 8 ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,Apoptosis ,Immunology ,medicine ,Molecular Biology ,medicine.drug ,Coronavirus - Abstract
Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.
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- 2020
24. A comprehensive guide to studying inflammasome activation and cell death
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Rebecca E. Tweedell, R. K. Subbarao Malireddi, and Thirumala-Devi Kanneganti
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Male ,Programmed cell death ,Inflammasomes ,Interleukin-1beta ,Cell ,Apoptosis ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Image Processing, Computer-Assisted ,medicine ,Animals ,030304 developmental biology ,0303 health sciences ,Innate immune system ,Cell Death ,L-Lactate Dehydrogenase ,Chemistry ,Macrophages ,Caspase 1 ,Interleukin-18 ,Pattern recognition receptor ,Inflammasome ,Immunity, Innate ,Neoplasm Proteins ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Female ,Inflammasome complex ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Inflammasomes are multimeric heterogeneous mega-Dalton protein complexes that play key roles in the host innate immune response to infection and sterile insults. Assembly of the inflammasome complex following infection or injury begins with the oligomerization of the upstream inflammasome-forming sensor and proceeds through a multistep process of well-coordinated events and downstream effector functions. Together, these steps enable elegant experimental readouts with which to reliably assess the successful activation of the inflammasome complex and cell death. Here, we describe a comprehensive protocol that details several in vitro (in bone marrow–derived macrophages) and in vivo (in mice) strategies for activating the inflammasome and explain how to subsequently assess multiple downstream effects in parallel to unequivocally establish the activation status of the inflammasome and cell death pathways. Our workflow assesses inflammasome activation via the formation of the apoptosis-associated speck-like protein containing a CARD (ASC) speck; cleavage of caspase-1 and gasdermin D; release of IL-1β, IL-18, caspase-1, and lactate dehydrogenase from the cell; and real-time analysis of cell death by imaging. Analyses take up to ~24 h to complete. Overall, our multifaceted approach provides a comprehensive and consistent protocol for assessing inflammasome activation and cell death. This protocol describes a toolbox for comprehensive characterization of inflammasome activation and cell death in response to both in vivo (in mice) and in vitro (using bone marrow–derived macrophages) models of infection, sterile insults, and cancer.
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- 2020
25. The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)
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Min Zheng and Thirumala-Devi Kanneganti
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0301 basic medicine ,Programmed cell death ,Inflammasomes ,Necroptosis ,Immunology ,Apoptosis ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,Pyroptosis ,medicine ,Influenza A virus ,Immunology and Allergy ,Innate immune system ,integumentary system ,RNA-Binding Proteins ,Inflammasome ,Cell biology ,Crosstalk (biology) ,030104 developmental biology ,Type I interferon signaling pathway ,030215 immunology ,medicine.drug - Abstract
ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z-RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co-regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1-NLRP3 inflammasome. When Z-RNA is sensed, ZBP1 recruits RIPK3 and caspase-8 to activate the ZBP1-NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1-NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase-6. Additionally, influenza viral proteins, such as M2, NS1, and PB1-F2, have also been shown to regulate the ZBP1-NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1-NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1-NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.
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- 2020
26. DDX3X Sits at the Crossroads of Liquid–Liquid and Prionoid Phase Transitions Arbitrating Life and Death Cell Fate Decisions in Stressed Cells
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Parimal Samir and Thirumala-Devi Kanneganti
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0301 basic medicine ,Cell ,Cell fate determination ,Biology ,DNACB Bit ,DEAD-box RNA Helicases ,03 medical and health sciences ,0302 clinical medicine ,Stress granule ,Genetics ,medicine ,Animals ,Humans ,Stress granule assembly ,Molecular Biology ,Innate immune system ,Cell Death ,integumentary system ,Inflammasome ,Receptor Cross-Talk ,Cell Biology ,General Medicine ,Cell biology ,Crosstalk (biology) ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Signal transduction ,Signal Transduction ,medicine.drug - Abstract
The crosstalk between cellular stress responses and innate immune signaling pathways remains poorly understood. Cells can respond to stressors by assembling stress granules that store 40S ribosomes, translation initiation factors, and mRNAs, and allow the cell to survive. Some stressors can activate the NLRP3 inflammasome, which leads to pyroptotic cell death. Stress granules and the NLRP3 inflammasome provide distinct cell fate choices to the cell. These complexes also involve distinct types of phase transitions-liquid-liquid phase separation for stress granules and prionoid phase transition for the NLRP3 inflammasome. We recently reported that DDX3X modulates this crosstalk by acting as a common essential factor for NLRP3 inflammasome activation and stress granule assembly. Here, we discuss the role of DDX3X in modulating the liquid-liquid phase separation and prionoid phase transition required for making cell fate decisions under stress conditions.
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- 2020
27. Caspases in Cell Death, Inflammation, and Pyroptosis
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Sannula Kesavardhana, R. K. Subbarao Malireddi, and Thirumala-Devi Kanneganti
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0301 basic medicine ,Proteases ,Programmed cell death ,Immunology ,Apoptosis ,Inflammation ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pyroptosis ,medicine ,Animals ,Humans ,Immunology and Allergy ,Caspase ,Innate immune system ,Cell Death ,biology ,Inflammasome ,Neoplasm Proteins ,Cell biology ,Enzyme Activation ,Multicellular organism ,030104 developmental biology ,Caspases ,030220 oncology & carcinogenesis ,biology.protein ,Disease Susceptibility ,medicine.symptom ,Biomarkers ,Signal Transduction ,medicine.drug - Abstract
Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D–induced pyroptosis.
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- 2020
28. The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis
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Thirumala-Devi Kanneganti, Balaji Banoth, Tejasvi Krishna Dasari, Bhesh Raj Sharma, Amanda R. Burton, Rechel Geiger, Prajwal Gurung, and Rajendra Karki
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0301 basic medicine ,Inflammasomes ,Interleukin-1beta ,Syk ,Biology ,Caspase 8 ,Biochemistry ,03 medical and health sciences ,AIM2 ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Syk Kinase ,Protein kinase A ,Molecular Biology ,Inflammation ,030102 biochemistry & molecular biology ,Chronic recurrent multifocal osteomyelitis ,NF-kappa B ,Osteomyelitis ,Inflammasome ,Cell Biology ,medicine.disease ,Cell biology ,CARD Signaling Adaptor Proteins ,DNA-Binding Proteins ,Mice, Inbred C57BL ,030104 developmental biology ,Receptor-Interacting Protein Serine-Threonine Kinases ,Disease Progression ,Editors' Picks Highlights ,Signal transduction ,Tyrosine kinase ,Signal Transduction ,medicine.drug - Abstract
Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline–serine–threonine phosphatase–interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo. However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in Pstpip2cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain–containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in Pstpip2cmo mice, thereby inducing cmo. These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.
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- 2020
29. Inflammasomes and the fine line between defense and disease
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Shelbi Christgen and Thirumala-Devi Kanneganti
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0301 basic medicine ,NLRP6 ,Inflammasomes ,Extramural ,Immunology ,Inflammasome ,Disease ,Biology ,Fine line ,Article ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,030215 immunology ,medicine.drug ,Interferon regulatory factors - Abstract
Recognition of invading pathogens and execution of defensive responses are crucial steps in successfully combating infectious diseases. Inflammasomes are a group of diverse, signal-transducing complexes with key roles in both processes. While the responses mediated by inflammasomes are vital to host defense, aberrations in inflammasome regulation or activity can lead to the development of autoimmune and sterile inflammatory diseases, including cancer. The field of inflammasome research has rapidly expanded to identify novel regulatory pathways, new inflammasome components, and the mechanistic details of the activation of these complexes. In this review, we discuss recent insights into the regulation of inflammasomes by interferon regulatory factor proteins, newly discovered mechanisms of activation for the NLRP1b and NLRP6 inflammasomes, and recent studies exploring the viability of inflammasome-modulating immunotherapies.
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- 2020
30. Fungal cell wall components modulate our immune system
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Nicolas Papon, Benoit Briard, Thierry Fontaine, Neil A. R. Gow, Thirumala-Devi Kanneganti, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), St Jude Children's Research Hospital, University of Aberdeen, University of Exeter, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Université de Brest (UBO), NG acknowledges welcome support of a Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z, 215599/Z/19/Z) and Strategic Awards (097377/Z11/Z) and the MRC Centre for Medical Mycology [MR/N006364/2]., Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), and Fontaine, Thierry
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Host immunity ,Cell death ,[SDV]Life Sciences [q-bio] ,Galactosaminogalactan ,Trained immunity ,Biology ,Skin infection ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Applied Microbiology and Biotechnology ,Microbiology ,Article ,Inflammasome ,Cell wall ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Polysaccharides ,Melanin ,medicine ,Pyroptosis ,PANoptosis ,[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Innate immunity ,0303 health sciences ,Immunometabolism ,Innate immune system ,QH573-671 ,030306 microbiology ,Cell Biology ,medicine.disease ,3. Good health ,chemistry ,Immunology ,Cytology ,medicine.drug - Abstract
International audience; Invasive fungal infections remain highly problematic for human health. Collectively, they account for more than 1 million deaths a year in addition to more than 100 million mucosal infections and 1 billion skin infections. To be able to make progress it is important to understand the pathobiology of fungal interactions with the immune system. Here, we highlight new advancements pointing out the pivotal role of fungal cell wall components (β-glucan, mannan, galactosaminogalactan and melanin) in modulating host immunity and discuss how these open new opportunities for the development of immunomodulatory strategies to combat deadly fungal infectious diseases.
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- 2021
31. Galactosaminogalactan activates the inflammasome to provide host protection
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Emilia Mellado, Jean-Paul Latgé, Parimal Samir, Shelbi Christgen, Thierry Fontaine, Cam Robinson, R. K. Subbarao Malireddi, Rajendra Karki, Laetitia Muszkieta, David E. Place, Perrine Bomme, Rémi Beau, Ravi C. Kalathur, Thirumala-Devi Kanneganti, Oumaïma Ibrahim-Granet, Benoit Briard, Bernard Henrissat, Peter Vogel, St. Jude Children’s Research Hospital [Memphis], Aspergillus, Institut Pasteur [Paris], Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Instituto de Salud Carlos III [Madrid] (ISC), Cytokines et Inflammation, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King Abdulaziz University, We thank members of the Kanneganti laboratory for their comments, suggestions and technical assistance, R. Tweedell for scientific editing of the manuscript, the St Jude Children’s Research Hospital Veterinary Pathology Core, SJCRH Center for Proteomics and Metabolomics and SJCRH Cell and Tissue Imaging Center (supported by the NCI P30 CA021765), D. Sheppard for sharing the A. fumigatus deletion mutant ∆agd, and V. M. Dixit and N. Kayagaki for the Casp1−/−Casp11−/− mutant mouse strain. T.-D.K. is supported by NIH grants AI101935, AI124346, AR056296 and CA253095 and by the American Lebanese Syrian Associated Charities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.-P.L. is supported by the Aviesan project Aspergillus, the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant number ANR-10-LABX-62-IBEID) and la Fondation pour la Recherche Médicale (DEQ20150331722 LATGE Equipe FRM 2015)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), St Jude Children's Research Hospital, and Institut Pasteur [Paris] (IP)
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Male ,Inflammasomes ,[SDV]Life Sciences [q-bio] ,Galactosaminogalactan ,caspase-1 ,Ribosome ,Inflammasome ,Aspergillus fumigatus ,chemistry.chemical_compound ,Mice ,Protein biosynthesis ,innate immunity ,GAG ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,Dextran Sulfate ,Translation (biology) ,Colitis ,galactosaminogalactan ,3. Good health ,Cell biology ,host defense ,Female ,medicine.drug ,Ribosomal Proteins ,Article ,Fungal Proteins ,03 medical and health sciences ,NLRP3 ,Ribosomal protein ,Polysaccharides ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Aspergillosis ,030304 developmental biology ,Innate immune system ,030306 microbiology ,Pathogen-Associated Molecular Pattern Molecules ,biology.organism_classification ,Immunity, Innate ,Biofilms ,Protein Biosynthesis ,fungi ,Ribosomes ,Gene Deletion - Abstract
International audience; Galactosaminogalactan of Aspergillus fumigatus acts as a pathogen-associated molecular pattern that activates the NLRP3 inflammasome, which is crucial for anti-fungal host defence.Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs)(1). Activation of the inflammasome provides host defence against aspergillosis(2,3), which is a major health concern for patients who are immunocompromised. However, the Aspergillus fumigatus PAMPs that are responsible for inflammasome activation are not known. Here we show that the polysaccharide galactosaminogalactan (GAG) of A. fumigatus is a PAMP that activates the NLRP3 inflammasome. The binding of GAG to ribosomal proteins inhibited cellular translation machinery, and thus activated the NLRP3 inflammasome. The galactosamine moiety bound to ribosomal proteins and blocked cellular translation, which triggered activation of the NLRP3 inflammasome. In mice, a GAG-deficient Aspergillus mutant (Delta gt4c) did not elicit protective activation of the inflammasome, and this strain exhibited enhanced virulence. Moreover, administration of GAG protected mice from colitis induced by dextran sulfate sodium in an inflammasome-dependent manner. Thus, ribosomes connect the sensing of this fungal PAMP to the activation of an innate immune response.
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- 2020
32. NLRP3 inflammasome activation triggers gasdermin D–independent inflammation
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Gabriel Mbalaviele, Yael Alippe, Jianqiu Xiao, Tong Yang, Thirumala-Devi Kanneganti, Joseph B. Monahan, Kai Sun, Yousef Abu-Amer, Canxin Xu, Judy Lieberman, and Chun Wang
- Subjects
Pore Forming Cytotoxic Proteins ,Inflammasomes ,Immunology ,Mice, Transgenic ,Inflammation ,Pyrin domain ,Article ,Mice ,Mice, Congenic ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Receptor ,Pathogen ,Cells, Cultured ,Mice, Knockout ,integumentary system ,Chemistry ,A protein ,Gasdermin D ,Inflammasome ,General Medicine ,Phosphate-Binding Proteins ,Cell biology ,NLRP3 inflammasome activation ,medicine.symptom ,medicine.drug - Abstract
NOD-like receptor (NLR), family pyrin domain containing 3 (NLRP3) assembles an intracellular protein complex known as the NLRP3 inflammasome upon sensing certain pathogen products or sterile danger signals. Gain-of-function mutations such as the D301N substitution in NLRP3, which cause its constitutive activation (NLRP3(CA)) also results in inflammasome assembly. This inflammasome processes pro-interleukin-1 β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively, and cleaves gasdermin D (GSDMD). GSDMD N-terminal fragments form plasma membrane pores that facilitate the secretion of IL-1β and IL-18 and lead to the inflammatory cell death pyroptosis. Accordingly, GSDMD inactivation results in negligible spontaneous inflammation in various experimental models such as in Nlrp3(CA/+) mice lacking GSDMD (Nlrp3(CA/+);Gsdmd(−/−) mice). Here, we found that Nlrp3(CA/+);Gsdmd(−/−) mice, when challenged with LPS or TNF-α, still secreted IL-1β and IL-18, indicating inflammasome activation independent of GSDMD. Accordingly, Gsdmd(−/−) macrophages failed to secrete IL-1β and undergo pyroptosis when briefly exposed to NLRP3 inflammasome activators (LPS and nigericin), but released these cytokines when persistently activated. Sustained NLRP3 inflammasome induced caspase-8/−3 and GSDME cleavage, and IL-1β maturation in vitro in Gsdmd(−/−) macrophages. Thus, a salvage inflammatory pathway involving caspase-8/−3-GSDME was activated following NLRP3 activation when the canonical NLRP3-GSDMD signaling was blocked. Consistent with genetic data, the active metabolite of FDA-approved disulfiram CuET, which inhibited GSDMD and GSDME cleavage in macrophages, reduced the severe inflammation and tissue damage that occurred in the Nlrp3(CA) mice. Thus, NLRP3 inflammasome activation overwhelms the protection afforded by GSDMD deficiency, rewiring signaling cascades through mechanisms that include GSDME to propagate inflammation.
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- 2021
33. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis
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R. K. Subbarao Malireddi, Balamurugan Sundaram, Peter Vogel, Geoffrey Neale, Bhesh Raj Sharma, Lam Nhat Nguyen, SangJoon Lee, Shelbi Christgen, Rajendra Karki, Thirumala-Devi Kanneganti, Yaqiu Wang, Min Zheng, and Parimal Samir
- Subjects
Male ,Programmed cell death ,Skin Neoplasms ,Adenosine Deaminase ,QH301-705.5 ,Necroptosis ,Melanoma, Experimental ,necroptosis ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,Interferon-gamma ,Antineoplastic Combined Chemotherapy Protocols ,ADAR1 ,medicine ,Animals ,Humans ,Biology (General) ,Nuclear export signal ,Mice, Knockout ,Cell Death ,pyroptosis ,Pyroptosis ,apoptosis ,RNA ,RNA-Binding Proteins ,Inflammasome ,ZBP1 ,Triazoles ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,tumorigenesis ,Cell Transformation, Neoplastic ,HEK293 Cells ,Hydrazines ,Apoptosis ,Receptor-Interacting Protein Serine-Threonine Kinases ,Cancer research ,Female ,Carcinogenesis ,Colorectal Neoplasms ,medicine.drug ,Signal Transduction - Abstract
Summary: Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.
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- 2021
34. The IFN-inducible GTPase IRGB10 regulates viral replication and inflammasome activation during influenza A virus infection in mice
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Min Zheng, Shelbi Christgen, Masahiro Yamamoto, Thirumala-Devi Kanneganti, David E. Place, and Benoit Briard
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Mice, Knockout ,Inflammasomes ,Immunology ,Pyroptosis ,Inflammasome ,Context (language use) ,GTPase ,Biology ,medicine.disease_cause ,Virus Replication ,Article ,Microbiology ,GTP Phosphohydrolases ,Mice ,Influenza A Virus, H1N1 Subtype ,Viral replication ,Orthomyxoviridae Infections ,Interferon ,medicine ,Influenza A virus ,Immunology and Allergy ,Animals ,IRGs ,medicine.drug - Abstract
The upregulation of interferon (IFN)-inducible GTPases in response to pathogenic insults is vital to host defense against many bacterial, fungal, and viral pathogens. Several IFN-inducible GTPases play key roles in mediating inflammasome activation and providing host protection after bacterial or fungal infections, though their role in inflammasome activation after viral infection is less clear. Among the IFN-inducible GTPases, the expression of immunity-related GTPases (IRGs) varies widely across species for unknown reasons. Here, we report that IRGB10, but not IRGM1, IRGM2, or IRGM3, is required for NLRP3 inflammasome activation in response to influenza A virus (IAV) infection. While IRGB10 functions to release inflammasome ligands in the context of bacterial and fungal infections, we found that IRGB10 facilitates endosomal maturation and nuclear translocation and viral replication of IAV. Corresponding with our in vitro results, we found that Irgb10-/- mice were more resistant to IAV-induced mortality than wild-type mice. The results of our study demonstrate a detrimental role of IRGB10 in host immunity in response to IAV and a novel function of IRGB10, but not IRGMs, in promoting viral translocation into the nucleus. This article is protected by copyright. All rights reserved.
- Published
- 2021
35. PANoptosis in viral infection: The missing puzzle piece in the cell death field
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Lam Nhat Nguyen and Thirumala-Devi Kanneganti
- Subjects
Cell death ,Programmed cell death ,Necroptosis ,Viral pathogenesis ,viruses ,Apoptosis ,Review Article ,Biology ,Models, Biological ,Virus ,Inflammasome ,Structural Biology ,medicine ,otorhinolaryngologic diseases ,Pyroptosis ,Animals ,Humans ,PANoptosis ,Molecular Biology ,Inflammation ,Innate immune system ,PANoptosome ,Virology ,respiratory tract diseases ,Crosstalk (biology) ,Viral infection ,Virus Diseases ,medicine.drug - Abstract
In the past decade, emerging virus outbreaks like SARS-CoV-2, Zika and Ebola have presented major challenges to the global health system. Viruses are unique pathogens in that they fully rely on the host cell to complete their lifecycle and potentiate disease. Therefore, programmed cell death (PCD), a key component of the host innate immune response, is an effective strategy for the host cell to curb viral spread. The most well-established PCD pathways, pyroptosis, apoptosis and necroptosis, can be activated in response to viruses. Recently, extensive crosstalk between PCD pathways has been identified, together with evidence that molecules from all three PCD pathways can be activated during virus infection. These findings have led to the emergence of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. While PCD is important to eliminate infected cells, many viruses are equipped to hijack host PCD pathways to benefit their own propagation and subvert host defense, and PCD can also lead to the production of inflammatory cytokines and inflammation. Therefore, viral infection can induce PANoptosis to contribute to either host defense or viral pathogenesis, depending on the virus. In this review, we will discuss the multi-faceted roles of PCD pathways in controlling viral infections.
- Published
- 2021
36. Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease
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Lukens, John R. and Kanneganti, Thirumala-Devi
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- 2014
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37. Filoviruses: Innate Immunity, Inflammatory Cell Death, and Cytokines.
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Lu, Jianlin, Gullett, Jessica M., and Kanneganti, Thirumala-Devi
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INTERFERON receptors ,NATURAL immunity ,CELL death ,FILOVIRIDAE ,PATTERN perception receptors ,RNA viruses - Abstract
Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics. [ABSTRACT FROM AUTHOR]
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- 2022
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- View/download PDF
38. Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression.
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Malireddi, R. K. Subbarao, Bynigeri, Ratnakar R., Kancharana, Balabhaskararao, Sharma, Bhesh Raj, Burton, Amanda R., Pelletier, Stephane, and Kanneganti, Thirumala-Devi
- Subjects
GENE expression ,KNOCKOUT mice ,GENETIC models ,INFLAMMATORY mediators ,INFLAMMASOMES - Abstract
Interleukin 1α (IL-1α) and IL-1β are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse (Il1a-KO
line1 ), showing reduced IL-1β expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice (Il1a-KOline2 ) using CRISPR-Cas9 technology. In contrast to cells from Il1a-KOline1 , where IL-1β expression was drastically reduced, bone marrow-derived macrophages (BMDMs) from Il1a-KOline2 mice showed normal induction and activation of IL-1β. Additionally, Il1a-KOline2 BMDMs showed normal inflammasome activation and IL-1β expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, using Il1a-KOline2 cells, we confirmed that IL-1α, independent of IL-1β, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1β. Future studies on the unique functions of IL-1α and IL-1β using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
39. Hierarchical Cell Death Program Disrupts the Intracellular Niche Required for Burkholderia thailandensis Pathogenesis
- Author
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Thirumala-Devi Kanneganti, Shelbi Christgen, Shraddha Tuladhar, R. K. Subbarao Malireddi, Peter Vogel, and David E. Place
- Subjects
Male ,caspase-3 ,caspase-11 ,Burkholderia thailandensis ,caspase-1 ,Apoptosis ,caspase-7 ,caspase-8 ,Mice ,0302 clinical medicine ,0303 health sciences ,biology ,gasdermin D ,Pyroptosis ,Respiratory infection ,Burkholderia Infections ,QR1-502 ,T6SS ,Caspases ,Female ,VgrG5 ,Research Article ,MLKL ,Programmed cell death ,RIPK1 ,Burkholderia ,Necroptosis ,Caspase 1 ,necroptosis ,macrophage ,Caspase-11 ,RIPK3 ,Microbiology ,03 medical and health sciences ,NLRP3 ,inflammasome ,Virology ,Animals ,PANoptosis ,030304 developmental biology ,NLRC4 ,cell fusion ,Macrophages ,PANoptosome ,biology.organism_classification ,Immunity, Innate ,virulence ,type six secretion system ,030215 immunology - Abstract
Burkholderia infections can result in serious diseases with high mortality, such as melioidosis, and they are difficult to treat with antibiotics. Innate immunity is critical for cell-autonomous clearance of intracellular pathogens like Burkholderia by regulating programmed cell death. Inflammasome-dependent inflammatory cytokine release and cell death contribute to host protection against Burkholderia pseudomallei and Burkholderia thailandensis; however, the contribution of apoptosis and necroptosis to protection is not known. Here, we found that bone marrow-derived macrophages (BMDMs) lacking key components of pyroptosis died via apoptosis during infection. BMDMs lacking molecules required for pyroptosis, apoptosis, and necroptosis (PANoptosis), however, were significantly resistant to B. thailandensis-induced cell death until later stages of infection. Consequently, PANoptosis-deficient BMDMs failed to limit B. thailandensis-induced cell-cell fusion, which permits increased intercellular spread and replication compared to wild-type or pyroptosis-deficient BMDMs. Respiratory B. thailandensis infection resulted in higher mortality in PANoptosis-deficient mice than in pyroptosis-deficient mice, indicating that, in the absence of pyroptosis, apoptosis is essential for efficient control of infection in vivo. Together, these findings suggest both pyroptosis and apoptosis are necessary for host-mediated control of Burkholderia infection. IMPORTANCE Burkholderia infections result in a high degree of mortality when left untreated; therefore, understanding the host immune response required to control infection is critical. In this study, we found a hierarchical cell death program utilized by infected cells to disrupt the intracellular niche of Burkholderia thailandensis, which limits bacterial intercellular spread, host cell-cell fusion, and bacterial replication. In macrophages, combined loss of key PANoptosis components results in extensive B. thailandensis infection-induced cell-cell fusion, bacterial replication, and increased cell death at later stages of infection compared with both wild-type (WT) and pyroptosis-deficient cells. During respiratory infection, mortality was increased in PANoptosis-deficient mice compared to pyroptosis-deficient mice, identifying an essential role for multiple cell death pathways in controlling B. thailandensis infection. These findings advance our understanding of the physiological role of programmed cell death in controlling Burkholderia infection.
- Published
- 2021
40. Role of AIM2 inflammasome in inflammatory diseases, cancer and infection
- Author
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Thirumala-Devi Kanneganti, Rajendra Karki, and Bhesh Raj Sharma
- Subjects
0301 basic medicine ,Programmed cell death ,Inflammasomes ,Interleukin-1beta ,Immunology ,Gut flora ,Skin Diseases ,Article ,03 medical and health sciences ,AIM2 ,0302 clinical medicine ,Diabetes Mellitus ,Pyroptosis ,medicine ,Animals ,Humans ,Immunology and Allergy ,Secretion ,Renal Insufficiency, Chronic ,Innate immune system ,biology ,Effector ,Interleukin-18 ,Inflammasome ,Bacterial Infections ,DNA ,biology.organism_classification ,Cell biology ,DNA-Binding Proteins ,030104 developmental biology ,Gene Expression Regulation ,Mycoses ,Cardiovascular Diseases ,Virus Diseases ,Colorectal Neoplasms ,030215 immunology ,medicine.drug - Abstract
AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.
- Published
- 2019
41. Differential role of the <scp>NLRP</scp> 3 inflammasome in infection and tumorigenesis
- Author
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Sarang Tartey and Thirumala-Devi Kanneganti
- Subjects
Carcinogenesis ,Inflammasomes ,Immunology ,Inflammation ,Nod ,Infections ,Immune system ,Neoplasms ,NOD2 ,NLR Family, Pyrin Domain-Containing 3 Protein ,NOD1 ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Review Articles ,integumentary system ,business.industry ,Cancer ,Inflammasome ,medicine.disease ,Cancer research ,medicine.symptom ,business ,Periodic fever syndrome ,medicine.drug - Abstract
Dysregulated inflammation is one of the hallmarks of cancer initiation and progression. Emerging evidence indicates that inflammasomes play a central role in regulating immune cell functions in various infections and cancer. Inflammasomes are multimeric complexes consisting of nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs). Among the NLRs, NOD1, NOD2 and NLRP3 respond to a variety of endogenous (i.e. damage-associated molecular patterns) and exogenous (i.e. pathogen-associated molecular patterns) stimuli. The NLRP3 inflammasome is associated with the onset and progression of autoinflammatory and autoimmune diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, and cryopyrin-associated periodic fever syndrome. NLRP3 is also associated with a wide variety of infections and tumorigenesis that are closely correlated with chemotherapy response and prognosis. In this review, we explore the rapidly expanding body of research on the expression and functions of NLRP3 in infections and cancers and outline novel inhibitors targeting the NLRP3 inflammasome that could be developed as therapeutic alternatives to current anticancer treatment.
- Published
- 2019
42. Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida
- Author
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Arjun Balakrishnan, Thirumala-Devi Kanneganti, Rajendra Karki, Min Zheng, and Qifan Zhu
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Programmed cell death ,Inflammasomes ,Interleukin-1beta ,Immunology ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,AIM2 ,0302 clinical medicine ,Pyroptosis ,medicine ,Animals ,Immunology and Allergy ,Francisella novicida ,Francisella tularensis ,Receptor ,Cells, Cultured ,Mice, Knockout ,Receptors, Interleukin-1 Type I ,Macrophages ,Caspase 1 ,Interleukin-18 ,Intracellular Signaling Peptides and Proteins ,Inflammasome ,Transfection ,Phosphate-Binding Proteins ,bacterial infections and mycoses ,Cell biology ,DNA-Binding Proteins ,Mice, Inbred C57BL ,030104 developmental biology ,Female ,Apoptosis Regulatory Proteins ,Gram-Negative Bacterial Infections ,Inflammasome complex ,030215 immunology ,medicine.drug - Abstract
The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to Francisella tularensis subspecies novicida infection, leading to maturation of IL-1b and IL-18 and pyroptosis. AIM2 is critical for host protection against F. novicida infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase-1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to F. novicida infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in F. novicida–infected bone marrow–derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow–derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome.
- Published
- 2018
43. Is Inflammasome a Potential Target of Prophylaxis in Rheumatic Heart Disease?
- Author
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Teneema Kuriakose and Thirumala-Devi Kanneganti
- Subjects
0301 basic medicine ,Heart disease ,Inflammasomes ,Interleukin-1beta ,03 medical and health sciences ,Physiology (medical) ,medicine ,Humans ,Extramural ,business.industry ,Rheumatic Heart Disease ,Granulocyte-Macrophage Colony-Stimulating Factor ,Hydroxychloroquine ,Acute rheumatic fever ,Inflammasome ,medicine.disease ,030104 developmental biology ,Granulocyte macrophage colony-stimulating factor ,Immunology ,Rheumatic fever ,Rheumatic Fever ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Published
- 2018
44. TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy
- Author
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Clifford S. Guy, Deepika Sharma, Peter Vogel, Thirumala-Devi Kanneganti, and Ankit Malik
- Subjects
0301 basic medicine ,Inflammasomes ,Familial Mediterranean fever ,Inflammation ,Pyrin domain ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Receptors, Tumor Necrosis Factor, Type II ,Myeloid Cells ,Gene Knock-In Techniques ,Receptor ,Mice, Knockout ,Tumor Necrosis Factor-alpha ,business.industry ,Inflammasome ,General Medicine ,Pyrin ,medicine.disease ,MEFV ,030104 developmental biology ,Receptors, Tumor Necrosis Factor, Type I ,Immunology ,Tumor necrosis factor alpha ,medicine.symptom ,business ,Research Article ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
Pyrin is an inflammasome sensor that promotes caspase-1–mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (Mefv(V726A/V726A)) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.
- Published
- 2018
45. DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response
- Author
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Min Zheng, Parimal Samir, Rajendra Karki, Benoit Briard, David E. Place, R. K. Subbarao Malireddi, Thirumala-Devi Kanneganti, Bhesh Raj Sharma, Sannula Kesavardhana, and Peter Vogel
- Subjects
0301 basic medicine ,P-eIF2α, phosphorylation of eIF2α ,Inflammasomes ,NS1 ,CASP1, caspase-1 ,Biochemistry ,P-IRF3, phosphorylation of IRF3 ,DEAD-box RNA Helicases ,Mice ,iBMDMs, immortalized BMDMs ,Interferon ,innate immunity ,Ars, arsenite ,MCMV, murine cytomegalovirus ,NP, nucleoprotein ,STAT1, signal transducer and activator of transcription 1 ,MOI, multiplicity of infection ,Toll-like receptor ,RIG-I ,HRP, horseradish peroxidase ,Inflammasome ,CASP3, caspase-3 ,Cell biology ,G3BP1, GTPase-activating protein-binding protein 1 ,host defense ,Interferon Type I ,DDX3X ,medicine.drug ,Research Article ,TLR, Toll-like receptor ,VSV, vesicular stomatitis virus ,PR8, Puerto Rico/8/34 ,IRF1, interferon regulatory factor 1 ,Biology ,stress granule ,03 medical and health sciences ,Immune system ,Stress granule ,NLRP3 ,inflammasome ,NLR Family, Pyrin Domain-Containing 3 Protein ,CASP8, caspase-8 ,IAV, influenza A virus ,medicine ,Animals ,influenza A virus ,DDX3X, DEAD-box helicase 3 X-linked ,IFN, interferon ,Molecular Biology ,immune evasion ,NS1, nonstructural protein 1 ,Innate immune system ,ΔNS1, NS1 deletion mutant ,030102 biochemistry & molecular biology ,Cell Biology ,ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain ,SG, stress granule ,NLRP3, nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 ,Immunity, Innate ,IL, interleukin ,RIG-I, retinoic acid–inducible gene I ,030104 developmental biology ,IRF1 ,BMDM, bone marrow–derived macrophage ,type I IFN - Abstract
Viruses and hosts have coevolved for millions of years, leading to the development of complex host-pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule-mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection.
- Published
- 2021
46. Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy
- Author
-
Jianqiu Xiao, Yousef Abu-Amer, Gabriel Mbalaviele, Joseph B. Monahan, Yael Alippe, Tong Yang, Thirumala-Devi Kanneganti, Judy Lieberman, Kai Sun, Canxin Xu, and Chun Wang
- Subjects
Mutation ,Chemistry ,medicine.medical_treatment ,Pyroptosis ,Gasdermin D ,Inflammation ,Inflammasome ,medicine.disease_cause ,In vitro ,Cell biology ,Cytokine ,Disulfiram ,medicine ,medicine.symptom ,medicine.drug - Abstract
The D301N NLRP3 mutation in mice (D303N in humans) causes severe multi-organ damage and early death driven by the constitutively activated NLRP3 (NLRP3ca) inflammasome. Triggered inflammasomes activate caspase-1 to process IL-1 family cytokines and gasdermin D (GSDMD), generating N-terminal fragments, which oligomerize within the plasma membrane to form pores, which cause inflammatory cell death (pyroptosis) and through which IL-1β and IL-18 are secreted. GSDMD activation is central to disease symptoms since spontaneous inflammation inNlrp3ca;Gsdmd-/-mice is negligible. Unexpectedly, whenNlrp3ca;Gsdmd-/-mice were challenged with LPS or TNF-α, they secreted high amounts of IL-1β and IL-18, suggesting an alternative GSDMD-independent inflammatory pathway. Here we show that GSDMD deficient macrophages subjected to inflammatory stimuli activate caspase-8, -3 and GSDME-dependent cytokine release and pyroptosis. Caspase-8, -3 and GSDME also activated pyroptosis when NLRP3 was stimulated in caspase-1 deficient macrophages. Thus, a salvage caspase-8, -3-GSDME inflammatory pathway is activated following NLRP3 activation when the canonical NLRP3-caspase-1-GSDMD is blocked. Surprisingly, the active metabolite of the GSDMD-inhibitor disulfiram, inhibited not only GSDMD but also GSDME-mediated inflammationin vitroand suppressed severe inflammatory disease symptoms inNlrp3camice, a model for severe neonatal multisystem inflammatory disease. Although disulfiram did not directly inhibit GSDME, it suppressed inflammasome activation in GSDMD-deficient cells. Thus, the combination of inflammatory signals and NLRP3caoverwhelmed the protection provided by GSDMD deficiency, rewiring signaling cascades through caspase-8, -3 and GSDME to propagate inflammation. This functional redundancy suggests that concomitant inhibition of GSDMD and GSDME may be necessary to suppress disease in inflammasomopathy patients.
- Published
- 2021
47. Newly Identified Function of Caspase-6 in ZBP1-mediated Innate Immune Responses, NLRP3 Inflammasome Activation, PANoptosis, and Host Defense
- Author
-
Min Zheng and Thirumala-Devi Kanneganti
- Subjects
RIPK1 ,Necroptosis ,Caspase 1 ,Apoptosis ,Caspase 6 ,Biology ,RIPK3 ,Caspase 8 ,Article ,Inflammasome ,NLRP3 ,Pyroptosis ,medicine ,PANoptosis ,Innate immunity ,Innate immune system ,ZBP1 ,PANoptosome ,Cell biology ,Influenza A virus ,Caspase-1 ,Caspase-8 ,Caspase-6 ,medicine.drug - Abstract
Caspase-6 was discovered decades ago, but its roles in biological processes remain largely unknown. Recently, we have demonstrated that caspase-6 plays a critical role in influenza A virus (IAV)-induced cell death and innate immune responses. During IAV infection, Z-DNA binding protein 1 (ZBP1) initiates ZBP1-PANoptosome assembly to drive inflammasome activation and cell death, and we showed that caspase-6 interacts with RIPK3 to enhance the interaction between RIPK3 and ZBP1, thus promoting PANoptosome assembly. Moreover, the caspase activity of caspase-6 is not required for tins process, suggesting a caspase-independent function of caspase-6 during IAV infection. Additionally, we found that caspase-6 is required for the alternative activation of alveolar macrophages in response to IAV infection. Our findings provide an opportunity to reconsider the physiological role of caspase-6.
- Published
- 2020
48. Innate Immune Cell Death in Neuroinflammation and Alzheimer's Disease.
- Author
-
Rajesh, Yetirajam and Kanneganti, Thirumala-Devi
- Subjects
- *
CELL death , *ALZHEIMER'S disease , *TAU proteins , *APOPTOSIS , *NEUROINFLAMMATION , *MICROGLIA , *PROGRAMMED cell death 1 receptors - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain's immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
49. DEAD/H-Box Helicases in Immunity, Inflammation, Cell Differentiation, and Cell Death and Disease.
- Author
-
Samir, Parimal and Kanneganti, Thirumala-Devi
- Subjects
- *
RNA metabolism , *CELL death , *HELICASES , *CELL differentiation , *APOPTOSIS , *DEAD , *HOMEOSTASIS , *BACTERIAL diseases - Abstract
DEAD/H-box proteins are the largest family of RNA helicases in mammalian genomes, and they are present in all kingdoms of life. Since their discovery in the late 1980s, DEAD/H-box family proteins have been a major focus of study. They have been found to play central roles in RNA metabolism, gene expression, signal transduction, programmed cell death, and the immune response to bacterial and viral infections. Aberrant functions of DEAD/H-box proteins have been implicated in a wide range of human diseases that include cancer, neurodegeneration, and inherited genetic disorders. In this review, we provide a historical context and discuss the molecular functions of DEAD/H-box proteins, highlighting the recent discoveries linking their dysregulation to human diseases. We will also discuss the state of knowledge regarding two specific DEAD/H-box proteins that have critical roles in immune responses and programmed cell death, DDX3X and DDX58, also known as RIG-I. Given their importance in homeostasis and disease, an improved understanding of DEAD/H-box protein biology and protein–protein interactions will be critical for informing strategies to counteract the pathogenesis associated with several human diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
50. It's All in the PAN: Crosstalk, Plasticity, Redundancies, Switches, and Interconnectedness Encompassed by PANoptosis Underlying the Totality of Cell Death-Associated Biological Effects.
- Author
-
Gullett, Jessica M., Tweedell, Rebecca E., and Kanneganti, Thirumala-Devi
- Subjects
APOPTOSIS ,CELL anatomy ,MOLECULAR interactions ,HOMEOSTASIS ,CELL death ,PYROPTOSIS ,MOLECULAR switches ,INFLUENZA - Abstract
The innate immune system provides the first line of defense against cellular perturbations. Innate immune activation elicits inflammatory programmed cell death in response to microbial infections or alterations in cellular homeostasis. Among the most well-characterized programmed cell death pathways are pyroptosis, apoptosis, and necroptosis. While these pathways have historically been defined as segregated and independent processes, mounting evidence shows significant crosstalk among them. These molecular interactions have been described as 'crosstalk', 'plasticity', 'redundancies', 'molecular switches', and more. Here, we discuss the key components of cell death pathways and note several examples of crosstalk. We then explain how the diverse descriptions of crosstalk throughout the literature can be interpreted through the lens of an integrated inflammatory cell death concept, PANoptosis. The totality of biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. We also discuss PANoptosomes, which are multifaceted macromolecular complexes that regulate PANoptosis. We consider the evidence for PANoptosis, which has been mechanistically characterized during influenza A virus, herpes simplex virus 1, Francisella novicida, and Yersinia infections, as well as in response to altered cellular homeostasis, in inflammatory diseases, and in cancers. We further discuss the role of IRF1 as an upstream regulator of PANoptosis and conclude by reexamining historical studies which lend credence to the PANoptosis concept. Cell death has been shown to play a critical role in infections, inflammatory diseases, neurodegenerative diseases, cancers, and more; therefore, having a holistic understanding of cell death is important for identifying new therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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