The nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome is essential in inflammation and inflammatory disorders. Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation. The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios, but the importance and regulation of this site has not been clarified. The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages. We also showed that Ser725 was directly phosphorylated by misshapen (Msn)/NIK-related kinase 1 (MINK1), depending on the direct interaction between MINK1 and the NLRP3 LRR domain. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis. Reactive oxygen species (ROS) upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation. Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner. Altogether, our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasome-related diseases.

核苷酸结合域、富含亮氨酸的重复序列家族、含有 pyrin 域的 3 (NLRP3) 炎性体在炎症和炎症性疾病中是必不可少的。NLRP3 上不同位点的磷酸化差异调节炎症小体的激活。NLRP3 上的 Ser725 磷酸化位点在多个炎性体激活场景中被描述，但该位点的重要性和调节尚未阐明。本研究表明，Ser725 的磷酸化是引发巨噬细胞中 NLRP3 炎性体的必要步骤。我们还发现 Ser725 被畸形 (Msn)/NIK 相关激酶 1 (MINK1) 直接磷酸化，这取决于 MINK1 和 NLRP3 LRR 结构域之间的直接相互作用。在急性败血症和腹膜炎小鼠模型中，MINK1 缺乏会降低 NLRP3 的活化并抑制炎症反应。活性氧 (ROS) 上调了 MINK1 的激酶活性，随后通过 NLRP3 Ser725 磷酸化促进了炎症小体的启动。消除 ROS 抑制了 NLRP3 的活化，并以 MINK1 依赖的方式减少了败血症和腹膜炎症状。总之，我们的研究揭示了 Msn 家族激酶 MINK1 对 NLRP3 炎性体的直接调节，并表明调节 MINK1 活性是炎性体相关疾病的潜在干预策略。消除 ROS 抑制了 NLRP3 的活化，并以 MINK1 依赖的方式减少了败血症和腹膜炎症状。总之，我们的研究揭示了 Msn 家族激酶 MINK1 对 NLRP3 炎性体的直接调节，并表明调节 MINK1 活性是炎性体相关疾病的潜在干预策略。消除 ROS 抑制了 NLRP3 的活化，并以 MINK1 依赖的方式减少了败血症和腹膜炎症状。总之，我们的研究揭示了 Msn 家族激酶 MINK1 对 NLRP3 炎性体的直接调节，并表明调节 MINK1 活性是炎性体相关疾病的潜在干预策略。