Inflammatory caspases (caspase-1, caspase-4, caspase-5 and caspase-11 (caspase-1/-4/-5/-11)) mediate host defense against microbial infections, processing pro-inflammatory cytokines and triggering pyroptosis. However, precise checkpoints are required to prevent their unsolicited activation. Here we report that serpin family B member 1 (SERPINB1) limited the activity of those caspases by suppressing their caspase-recruitment domain (CARD) oligomerization and enzymatic activation. While the reactive center loop of SERPINB1 inhibits neutrophil serine proteases, its carboxy-terminal CARD-binding motif restrained the activation of pro-caspase-1/-4/-5/-11. Consequently, knockdown or deletion of SERPINB1 prompted spontaneous activation of caspase-1/-4/-5/-11, release of the cytokine IL-1β and pyroptosis, inducing elevated inflammation after non-hygienic co-housing with pet-store mice and enhanced sensitivity to lipopolysaccharide- or Acinetobacter baumannii–induced endotoxemia. Our results reveal that SERPINB1 acts as a vital gatekeeper of inflammation by restraining neutrophil serine proteases and inflammatory caspases in a genetically and functionally separable manner.

炎性半胱天冬酶（caspase-1，caspase-4，caspase-5和caspase-11（caspase-1 / -4 / -5 / -11））介导宿主防御微生物感染，处理促炎性细胞因子并触发发烧。但是，需要精确的检查点以防止其未经请求的激活。在这里我们报告说，丝氨酸蛋白酶抑制剂家族B成员1（SERPINB1）通过抑制它们的胱天蛋白酶招募域（CARD）寡聚化和酶促活化作用限制了这些胱天蛋白酶的活性。尽管SERPINB1的反应性中心环抑制嗜中性丝氨酸蛋白酶，但其羧基末端CARD结合基序抑制了caspase-1 / -4 / -5 / -11的活化。因此，敲低或删除SERPINB1会促使caspase-1 / -4 / -5 / -11自发激活，释放细胞因子IL-1β并引起细胞凋亡，鲍曼不动杆菌引起的内毒素血症。我们的结果表明，SERPINB1通过以基因和功能上可分离的方式抑制嗜中性粒细胞丝氨酸蛋白酶和炎症性胱天蛋白酶来充当炎症的重要守门员。