TRIF signaling is required for caspase-11-dependent immune responses and lethality in sepsis

Tang, Yiting; Zhang, Rui; Xue, Qianqian; Meng, Ran; Wang, Xiangyu; Yang, Yanliang; Xie, Liling; Xiao, Xianzhong; Billiar, Timothy R.; Lü, Ben

doi:10.1186/s10020-018-0065-y

Cited by 24 publications

(19 citation statements)

References 25 publications

(53 reference statements)

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“…This form of cell death can be induced through 2 different signaling pathways: Caspase-1–dependent pyroptosis and Caspase-11–dependent noncanonical pyroptosis. While Caspase-1–mediated pyroptosis plays an important role in chronic autoimmune and other inflammatory diseases, Caspase-11–dependent noncanonical pyroptosis exacerbates pathologies in mouse models of sepsis ( 22 , 24 , 51 – 53 ). In this pathway, cytosolic LPS from Gram-negative bacterium activates Caspase-11 (Caspase-4/5 in humans) to cleave GSDMD, which then triggers cell membrane pore formation and cell death of macrophages ( 54 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

Tian¹,

Qu²,

Alam³

et al. 2020

JCI Insight

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Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2 –/– or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11–dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2 –/– , Pad4 deficiency enhanced activation of Caspase-11–dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.

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Section: Discussionmentioning

confidence: 99%

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

Tian¹,

Qu²,

Alam³

et al. 2020

JCI Insight

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“…3e). CASP11 is the central component of the non-canonical inflammasome, senses intracellular LPS and drives LPS-induced lethality in vivo [35][36][37][38][39]. Casp11 mRNA and protein were strongly induced by LPS in spleen and liver of WT mice, which was profoundly decreased in Tyk2 K923E and Tyk2 −/− mice (Fig.…”

Section: Tyk2 Promotes the Production Of Pro-inflammatory Cytokines Dmentioning

confidence: 96%

“…Type I IFNs promote the production of IL-1β during LPSinduced endotoxemia [38], whereas the contribution of IFNγ to CASP11-dependent IL-1β production in vivo is unknown. IL-1β and IL-18 levels were strongly reduced in LPS-treated Ifnar1 −/− and Ifngr1 −/− mice at 16 h after treatment (Fig.…”

Section: Type I Ifn and Ifnγ Promote The Production Of Il-1β And Il-1mentioning

confidence: 99%

“…Deletion of all GBPs on chromosome 3 (i.e. GBP1, GBP2, GBP3, GBP5 and GBP7) profoundly reduced the release of IL-1β during LPS-induced endotoxemia, whereas deletion of GBP2 alone had more modest effects [38,58]. However, GBP2 has a prominent role in CASP11 activation during Gram-negative bacterial infections [59].…”

Section: Type I Ifn and Ifnγ Promote The Production Of Il-1β And Il-1mentioning

confidence: 99%

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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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“…*P < 0.05, **P < 0.01, ***P < 0.001, and N.S., not significant, two-tailed Student t-test. (52) (Figure 6D). Compared with wild-type mice, Gate-16 −/− Gabarap −/− mice showed increased mortality during the CLP and markedly higher production of IL-1β and IL-6 in the peritoneal fluids ( Figures 6D-F).…”

Section: Mice In Sepsis Modelsmentioning

confidence: 99%

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

et al. 2020

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Sepsis is a life-threating multi-organ disease induced by host innate immunity to pathogen-derived endotoxins including lipopolysaccharide (LPS). Direct sensing of LPS by caspase-11 activates inflammasomes and causes lethal sepsis in mice. Inhibition of caspase-11 inflammasomes is important for the prevention of LPS-induced septic shock; however, whether a caspase-11 inflammasome-specific suppressive mechanism exists is unclear. Here we show that deficiency of GABARAP autophagy-related proteins results in over-activation of caspase-11 inflammasomes but not of canonical inflammasomes. Gate-16 −/− Gabarap −/− macrophages exhibited elevated guanylate binding protein 2 (GBP2)-dependent caspase-11 activation and inflammatory responses. Deficiency of GABARAPs resulted in formation of GBP2-containing aggregates that promote IL-1β production. High mortality after low dose LPS challenge in Gate-16 −/− Gabarap −/− mice primed with poly(I:C) or polymicrobial sepsis was ameliorated by compound GBP2 deficiency. These results reveal a critical function of Gate-16 and Gabarap to suppress GBP2-dependent caspase-11-induced inflammation and septic shock.

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TRIF signaling is required for caspase-11-dependent immune responses and lethality in sepsis

Cited by 24 publications

References 25 publications

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

TYK2 licenses non-canonical inflammasome activation during endotoxemia

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

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