Function and Regulation of Noncanonical Caspase-4/5/11 Inflammasome

Matikainen, Sampsa; Nyman, Tuula A.; Cypryk, Wojciech

doi:10.4049/jimmunol.2000373

Cited by 113 publications

(89 citation statements)

References 65 publications

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“…Both CASP4 and CASP5 are activated by cytosolic LPS and capable of inducing pyroptosis [34]. 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].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

TYK2 licenses non-canonical inflammasome activation during endotoxemia

et al. 2020

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“…The non-canonical pathway is activated by rodent caspase-11 and its human orthologs, caspase-4 and caspase-5 [24]. Interestingly, caspase-11 is less efficient in IL-1β and IL-18 processing than it is in GSDMD cleavage, and the caspases of the non-canonical pathway.…”

Section: Inflammasomes: Overviewmentioning

confidence: 99%

“…Interestingly, caspase-11 is less efficient in IL-1β and IL-18 processing than it is in GSDMD cleavage, and the caspases of the non-canonical pathway. This dual action also requires strict control to prevent pyroptosis [24]. One such control mechanism involves the transient receptor protein channel 1 (TRPC1), a non-selective ion channel, which is itself a substrate for caspase-11.…”

Section: Inflammasomes: Overviewmentioning

confidence: 99%

“…One such control mechanism involves the transient receptor protein channel 1 (TRPC1), a non-selective ion channel, which is itself a substrate for caspase-11. Potassium efflux through pannexin-1 channels is necessary for NLRP3 inflammasome activation and pyroptosis, and TRPC1 knockouts have demonstrated stronger inflammatory responses [24]. However, the relationship between TRPC1 and GSDMD and the exact TRPC1 mechanism of action are both currently unknown (Fig.…”

Section: Inflammasomes: Overviewmentioning

confidence: 99%

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Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Govindarajan

Vaccari

Keane

2020

J Neuroinflammation

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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), and it remains the most common immune-mediated disorder affecting the CNS. While the cause of MS is unclear, the underlying pathomechanisms are thought to be either destruction by autoimmune T cells or dysfunction of myelin-producing cells. Recent advances have indicated that inflammasomes contribute the etiology of MS. Inflammasomes are multiprotein complexes of the innate immune response involved in the processing of caspase-1, the activation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as the cell death-mediated mechanism of pyroptosis and the activation of the adaptive immune response. Here we review the literature to date on the role of different inflammasome signaling pathways in the pathogenesis of MS and how these pathways may be targeted to reduce deleterious inflammatory processes and improve outcomes in this patient population.

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“…Canonical NLRP3 inflammasome activation is followed by the proteolytic processing and secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which are important mediators of inflammatory response (3). It has been previously shown that several activators of the NLRP3 inflammasome trigger a robust vesicle-mediated protein secretion in human innate immune cells (4). This suggests that exosome secretion constitutes an essential part of the NLRP3 inflammasome-mediated immune response.…”

mentioning

confidence: 95%