Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
Elife. 2022 May 26;11:e75166. doi: 10.7554/eLife.75166.
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome, the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1β. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1β release triggered by mutated NLRP3. While K efflux was dispensable, Ca was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.
Cryopyrin 相关周期性综合征（CAPS）是一种由编码 cryopyrin 的 NLRP3 基因突变引起的自身炎症综合征。家族性冷自身炎症综合征是 CAPS 中最温和的形式，其特征是由 IL-1β 过度产生引起的冷诱导炎症。然而，突变的 NLRP3 如何在 CAPS 中引起炎性小体激活的分子机制尚不清楚。在这里，我们发现 CAPS 相关的 NLRP3 突变体形成对冷敏感的聚集物，作为炎性小体激活的支架。冷暴露促进炎性小体的组装，随后由突变的 NLRP3 引发 IL-1β 的释放。虽然钾 efflux 不是必需的，但钙对于突变的 NLRP3 介导的炎性小体组装是必需的。值得注意的是，在突变的 NLRP3 介导的炎性小体组装过程中诱导钙内流。此外，caspase-1 抑制可防止突变的 NLRP3 诱导的 Ca 内流和炎性小体组装，表明由突变的 NLRP3 触发的正向 Ca 内流循环。因此，突变的 NLRP3 形成对冷敏感的聚集物，以促进炎性小体组装，与经典的 NLRP3 炎性小体激活不同。
