Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis

Gao, Yulei; Zhai, Jianhua; Chai, Yifeng

doi:10.1155/2018/5823823

Cited by 114 publications

(87 citation statements)

References 66 publications

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“…An alternative explanation for the increased bacterial dissemination and mortality in LPS-challenged LysM Δ Commd10 mice may be that over-activation of caspases-1 and –11 in these mice facilitates pyroptosis. This lytic form of cell death releases DAMPs that can further incite multiple organ dysfunction and mortality, and also lead to deficiency in intestinal epithelial cells and various immunocytes ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function

et al. 2018

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Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.

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Section: Discussionmentioning

confidence: 99%

Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function

et al. 2018

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“…In particular, the NLRP3 inflammasome senses both PAMPs (ATP) and DAMPs (mtDNA), recruiting caspase‐1. This process contributes to activation of caspase‐1, production of inflammatory cytokines, and initiation of pyroptosis . Accumulating evidence suggests that inflammasome is involved in the pathogenesis of sepsis by triggering pyroptosis in a caspase‐1 dependent manner .…”

Section: Sting Signaling and Cell Deathmentioning

confidence: 99%

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

Knight

Ren

et al. 2018

Acta Physiologica

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Stimulator of interferons genes (STING) is an adaptor protein that plays a critical role in the secretion of type I interferons and pro-inflammatory cytokines in response to cytosolic nucleic acid. Recent research indicates the involvement of the STING pathway in uncontrolled inflammation, sepsis, and shock. STING signaling is significantly up-regulated in human sepsis, and STING agonists are sug-

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“…NETosis sequesters bacteria for pathogen inactivation ( 3 ), and pyroptosis is an antimicrobial response that mainly takes place in macrophages. Although uncontrolled immune cell death has recently been considered as a significant contributing factor to sepsis pathogenesis ( 4 – 6 ), it is presently unknown whether manipulation of the regulation of NETosis and/or pyroptosis influences sepsis progression.…”

Section: Introductionmentioning

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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Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis

Cited by 114 publications

References 66 publications

Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function

Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

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

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