Platelet NLRP6 protects from microvascular thrombosis in sepsis.

Abstract

Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. NLRP6 possesses both pro- and anti-inflammatory effects with cell-type- or tissue-specific functions. However, the role of cell-type-specific NLRP6 in sepsis remains poorly understood. In the present study, we detected NLRP6 expression in platelets. By using platelet-specific NLRP6 knockout mice and the cecal ligation and puncture model of sepsis, we demonstrated that deletion of platelet NLRP6 increased the mortality, enhanced microvascular thrombosis in the lung and liver, and promoted platelet activation, platelet-neutrophil interactions as well as the neutrophil extracellular traps (NETs) formation following sepsis. Platelet function analysis in vitro showed that deletion of NLRP6 enhanced platelet aggregation, activation, and granules release. In addition, NLRP6 deletion promoted platelet NF-κB signaling via sustaining TAB1 expression independent of the inflammasome. Moreover, inhibition of NF-κB signaling abolished the aggravated effects of the absence of platelet NLRP6 on the intravascular microthrombosis and NETs formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between TRIM21 and TAB1 in activated platelets, resulting in K48-linked polyubiquitination of TAB1 and subsequent degradation. Finally, sepsis plasma triggered TAB1 degradation mediated by NLRP6/TRIM21 in normal healthy platelets through TLR4/MyD88. Our study identifies a novel protective role of platelet NLRP6 in the microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.