Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1β and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.

胞质先天免疫传感器对于宿主防御和形成复合物至关重要，例如炎症小体和 PANoptosomes，可诱导炎症细胞死亡。传感器 NLRP12 与传染病和炎症性疾病有关，但其激活触发因素以及在细胞死亡和炎症中的作用仍不清楚。在这里，我们发现 NLRP12 响应血红素加 PAMP 或 TNF 驱动炎症小体和 PANoptosome 激活、细胞死亡和炎症。TLR2/4 介导的信号通过 IRF1 诱导Nlrp12表达，从而导致炎性体形成，从而诱导 IL-1β 和 IL-18 成熟。炎症小体还作为较大的 NLRP12-PANoptosome 的组成部分，通过 caspase-8/RIPK3 驱动炎症细胞死亡。在溶血模型中，Nlrp12的缺失可以保护小鼠免受急性肾损伤和死亡。总体而言，我们确定 NLRP12 是血红素加 PAMP 介导的 PANoptosis、炎症和病理学的重要胞质传感器，表明 NLRP12 和该途径中的分子是溶血和炎症性疾病的潜在药物靶标。