Platelet NLRP6 protects against microvascular thrombosis in sepsis

作者：Huimin Jiang, Shuang Chen, Xiang Gui, Y N Li, Yueyue Sun, Hui Zhu, Yue Dai, Jie Zhang, Xiaoqian Li, Wen Ju, Zhenyu Li, Lingyu Zeng, Kailin Xu, Jianlin Qiao · 发表于：Blood · 年份：2025 · DOI：10.1182/blood.2025028739 · 被引用次数：18 · 研究领域：Inflammasome and immune disorders、Heme Oxygenase-1 and Carbon Monoxide、Venous Thromboembolism Diagnosis and Management

ABSTRACT: 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 activ...