Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

Yi, Young-Su

doi:10.3390/ijms21082736

Cited by 37 publications

(35 citation statements)

References 42 publications

(65 reference statements)

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“…However, the relative contribution to the pathogenesis of endotoxemia or bacterial sepsis is unclear [74]. Studies in mice have highlighted the involvement of CASP11-dependent inflammation in a wide spectrum of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and neurodegenerative diseases [75]. Although there might be considerable redundancies in the functions of CASP4 and CASP5, our results raise the interesting possibility that inhibition of TYK2 may be an attractive therapeutic target for the treatment of CASP5-driven diseases.…”

Section: Discussionmentioning

confidence: 82%

TYK2 licenses non-canonical inflammasome activation during endotoxemia

et al. 2020

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The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptorassociated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrowderived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.

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Section: Discussionmentioning

confidence: 82%

TYK2 licenses non-canonical inflammasome activation during endotoxemia

et al. 2020

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“…Caspase-11 non-canonical inflammasomes are activated in response to intracellular LPS by the direct interaction between CARD of caspase-11 and the lipid A moiety of LPS. Upon activation, LPS-caspase-11 complexes are oligomerized, and caspase-11 inflammasomes induce the proteolytic processing of GSDMD, leading to N-GSDMD-mediated membrane pore formation and pyroptosis [ 11 , 12 , 14 , 22 ]. Interestingly, recent studies have demonstrated the functional crosstalk between the caspase-11 non-canonical and NLRP3 inflammasomes during inflammatory responses.…”

Section: Inflammasome-induced Inflammatory Responsesmentioning

confidence: 99%

“…Interestingly, recent studies have demonstrated the functional crosstalk between the caspase-11 non-canonical and NLRP3 inflammasomes during inflammatory responses. Caspase-11 activates the NLRP3 inflammasome by inducing K + efflux [ 12 , 15 , 42 , 43 ], and this causes proteolytic activation of caspase-1, leading to caspase-1-mediated maturation and secretion of IL-1β and IL-18, and N-GSDMD-mediated pyroptosis [ 12 , 15 , 22 , 44 , 45 ], which implies that canonical and non-canonical inflammasomes cooperate to induce inflammatory responses and that there may be functional crosstalk between non-canonical caspase-11 and other types of canonical inflammasomes during these responses.…”

Section: Inflammasome-induced Inflammatory Responsesmentioning

confidence: 99%

“…NLR family inflammasomes, including NLRP1, NLRP3, NLRC4, NLRP6, AIM2, and pyrin are canonical inflammasomes, and their regulatory roles in inflammatory responses and various human diseases have been extensively studied [ 17 , 18 , 19 ]. Non-canonical inflammasomes, mouse caspase-11 and human caspase-4/5, were recently identified and have been demonstrated to be activated in response to a unique ligand, LPS [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation

2021

IJMS

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Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases.

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“…The first review article by Yi summarized and discussed the current studies exploring the activation mechanisms and the regulatory roles of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 and caspase-5 non-canonical inflammasomes in the inflammatory response and human diseases [ 4 ]. This review provided insight into new strategies for the development of anti-inflammatory therapeutics against infectious and inflammatory diseases via targeting non-canonical inflammasomes.…”

mentioning

confidence: 99%

Editorial of Special Issue “Regulatory Roles of Inflammasomes in Human Diseases”

Yun

2021

IJMS

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Inflammation is an innate immunity protecting the body from pathogens and cellular damages and comprises two steps; 1) priming (preparatory step) and triggering (activation step). The key feature of the triggering step is the activation of inflammasomes that are intracellular protein complexes consisting of pattern recognition receptors and inflammatory molecules. Inflammasomes are activated in response to various ligands, leading to the caspase-1-mediated maturation and secretion of pro-inflammatory cytokines, IL-1β and IL-18 and the gasdermin D-mediated pyroptosis, an inflammatory form of cell death. Previous studies have demonstrated that inflammasome activation is a key determinant of inflammatory responses and many human diseases; therefore, inflammasomes have been attracted much attention as critical drug targets to prevent and treat various human diseases.

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Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

Cited by 37 publications

References 42 publications

TYK2 licenses non-canonical inflammasome activation during endotoxemia

TYK2 licenses non-canonical inflammasome activation during endotoxemia

Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation

Editorial of Special Issue “Regulatory Roles of Inflammasomes in Human Diseases”

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