Converging roles of caspases in inflammasome activation, cell death and innate immunity

Man, Si Ming; Kanneganti, Thirumala‐Devi

doi:10.1038/nri.2015.7

Cited by 548 publications

(482 citation statements)

References 197 publications

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“…13 In other immune cells other proteases may activate IL-1b, e.g., proteinase-3 in neutrophils, granzyme A in NK cells, chymase in mast cells, and metalloendopeptidase meprin A in epithelial cells. 5,14 Inflammasomes are cytosolic wheel-like complexes composed by the assembly of NACHT, LRR and PYD domains-containing proteins (NLRP), the linker molecule apoptosis-associated specklike protein (ASC), and caspase-1 ( Figure 2).…”

Section: Il-1bmentioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

204

152

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Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, independently of the inflammasome. Both IL-1a and IL-1b ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1a/b regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1a/IL-b-IL-1R system in kidney disease should be further explored.

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Section: Il-1bmentioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

204

152

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“…From an evolutionary perspective, pyroptosis of cells harboring intracellular bacteria or in which LPS has breached the plasma membrane is an effective means of eliminating an intracellular bacterial niche and activating the host through release of inflammatory mediators such as IL-1β, while sparing uninfected neighboring cells (13,(28)(29)(30). Thus, pyroptosis induced by inflammatory caspases 1/4/5/11 is an innate immune response distinct from the canonical inflammasome activation pathway via cell-surface TLR4 (11,(31)(32)(33)(34). However, caspase-11 can also be immunopathologic in sepsis (35).…”

Section: Introductionmentioning

confidence: 99%

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

Cheng¹,

Xiong²,

Ye³

et al. 2017

Journal of Clinical Investigation

340

348

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Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 1 2 5 jci.org Volume 127 Number 11 November 2017the complex process of inflammation involves multiple programmed cell death pathways, depending on the type and magnitude of the inciting stimulus and cell type. From an evolutionary perspective, pyroptosis of cells harboring intracellular bacteria or in which LPS has breached the plasma membrane is an effective means of eliminating an intracellular bacterial niche and activating the host through release of inflammatory mediators such as IL-1β, while sparing uninfected neighboring cells (13,(28)(29)(30). Thus, pyroptosis induced by inflammatory caspases 1/4/5/11 is an innate immune response distinct from the canonical inflammasome activation pathway via cell-surface TLR4 (11,(31)(32)(33)(34). However, caspase-11 can also be immunopathologic in sepsis (35). Caspase-11-deficient mice were protected in endotoxemic shock (10,11), suggesting that in the setting of an overwhelming inflammatory response, the potentially protective pyroptotic mechanism activates an exaggerated pathologic response due to overwhelming cell lysis. The role of the inflammatory caspases 4/5/11 in mediating cytoplasmic LPS signaling and pyroptosis has until now been primarily studied in macrophages or dendritic cells (11,12,14,28,32,36). Their role in destroying the endothelial barrier through widespread endothelial death and pathogenesis of ALI remains unknown. Here, we tested the hypothesis that lung ECs are a primary target for pyroptosis via intracellular sensing of LPS by the inflammatory caspases 4/5/11 and that endothelial pyroptosis is required for the induction of ALI. Results LPS in ECs induces pyroptotic cell death via activation of inflammatory cas...

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“…Pyroptosis is uniquely dependent on inflammatory caspases such as caspase-1, murine caspase-11, and its human homologs caspases-4 and -5. Caspase-1 is a central component of canonical NLRP3, NLRC4, AIM2, and pyrin inflammasomes, and its activation leads to proteolytic processing and secretion of proinflammatory cytokines IL-1 and IL-18 as well as to pyroptosis (Man and Kanneganti, 2016). Intracellular lipopolysaccharide (LPS) from gram-negative bacteria can directly bind caspases-4, -5, or -11, and the activation of these caspases causes pyroptosis and non-canonical inflammasome activation (Hagar et al, 2013;Kayagaki et al, 2013;Shi et al, 2014).…”

mentioning

confidence: 99%

Formation of membrane pores by gasdermin-N causes pyroptosis

2016

Sci. China Life Sci.

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Converging roles of caspases in inflammasome activation, cell death and innate immunity

Cited by 548 publications

References 197 publications

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

Formation of membrane pores by gasdermin-N causes pyroptosis

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