Platelet NLRP6 protects against microvascular thrombosis in sepsis Available to Purchase

• NLRP6 deletion enhances platelet NF-κB signaling and granule secretion, promotes microthrombosis, and shortens survival in sepsis.

• NLRP6 promotes K48-linked TAB1 polyubiquitination and subsequent degradation via TRIM21.

Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. The nucleotide-oligomerization domain–like receptor family pyrin domain containing 6 protein (NLRP6) possesses both proinflammatory and anti-inflammatory abilities with cell type–specific or tissue-specific functions. However, the role of cell type–specific NLRP6 in sepsis remains poorly understood. In this 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 trap (NET) formation after 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 transforming growth factor-β activated kinase 1–binding protein 1 (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 NET formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between tripartite motif–containing protein 21 (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 toll-like receptor 4/myeloid differentiation primary response 88. Our study identifies a novel protective role of platelet NLRP6 in microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.