The NLRP3 inflammasome is a critical component of innate immunity that defends the host from microbial infections. However, its aberrant activation contributes to the pathogenesis of several inflammatory diseases. Activation of the NLRP3 inflammasome induces the secretion of proinflammatory cytokines IL-1β and IL-18, and pyroptotic cell death. NLRP3 contains a leucine-rich repeat (LRR) domain at its C-terminus. Although posttranslational modifications in this LRR domain have been shown to regulate NLRP3 inflammasome activation, the role of the entire LRR domain in NLRP3 inflammasome activation remains controversial. Here, we generated mouse macrophages that express an endogenous NLRP3 mutant lacking the LRR domain. Deletion of the LRR domain diminished NLRP3 inflammasome activation in macrophages. Furthermore, using NLRP3-deficient macrophages that are reconstituted with NLRP3 mutants lacking the LRR domain, we found that deletion of the LRR domain inhibited NLRP3 inflammasome activation. Mechanistically, deletion of the LRR domain inhibited NLRP3 self-association, oligomerization, and interaction with the essential regulator NEK7. Our results demonstrate a critical role for the LRR domain in NLRP3 inflammasome activation.

NLRP3 炎性体是先天免疫的重要组成部分，可保护宿主免受微生物感染。然而，其异常激活导致了多种炎症性疾病的发病机制。NLRP3 炎症小体的激活诱导促炎细胞因子 IL-1β 和 IL-18 的分泌，以及焦亡细胞死亡。NLRP3 在其 C 末端含有富含亮氨酸的重复 (LRR) 结构域。尽管该 LRR 结构域的翻译后修饰已被证明可以调节 NLRP3 炎症小体激活，但整个 LRR 结构域在 NLRP3 炎症小体激活中的作用仍存在争议。在这里，我们生成了表达缺乏 LRR 结构域的内源 NLRP3 突变体的小鼠巨噬细胞。LRR 结构域的缺失减少了巨噬细胞中 NLRP3 炎性体的激活。此外，使用用缺乏LRR结构域的NLRP3突变体重建的NLRP3缺陷型巨噬细胞，我们发现LRR结构域的缺失抑制了NLRP3炎性体的激活。从机制上讲，LRR 结构域的缺失抑制了 NLRP3 的自缔合、寡聚化以及与重要调节因子 NEK7 的相互作用。我们的结果证明了 LRR 结构域在 NLRP3 炎性体激活中的关键作用。