The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
Immunity. 2012 Dec 14;37(6):1009-23. doi: 10.1016/j.immuni.2012.08.027. Epub 2012 Dec 6.
Cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and mortality. Here we define a role for Caspase-1-dependent death, known as pyroptosis, in infection-induced cytopenias by studying inflammasome activation in hematopoietic progenitor cells. The NLRP1a inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death. Active NLRP1a induced a lethal systemic inflammatory disease that was driven by Caspase-1 and IL-1β but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1β-driven inflammation, active NLRP1a triggered pyroptosis of hematopoietic progenitor cells resulting in leukopenia at steady state. During periods of hematopoietic stress induced by chemotherapy or lymphocytic choriomeningitis virus (LCMV) infection, active NLRP1a caused prolonged cytopenia, bone marrow hypoplasia, and immunosuppression. Conversely, NLRP1-deficient mice showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress.
细胞减少症是危及生命感染的关键预后指标，导致免疫抑制和死亡率增加。在这里，我们通过研究造血祖细胞中的炎症小体激活来定义 Caspase-1 依赖性死亡（称为细胞焦亡）在感染诱导的细胞减少症中的作用。NLRP1a 炎症小体在造血祖细胞中表达，其激活触发其细胞焦亡。活性 NLRP1a 诱导致命的全身性炎症疾病，该疾病由 Caspase-1 和 IL-1β 驱动，但不依赖于凋亡相关斑点样蛋白（ASC），并可通过 IL-18 改善。令人惊讶的是，在没有 IL-1β 驱动的炎症的情况下，活性 NLRP1a 引发造血祖细胞的细胞焦亡，导致稳态时白细胞减少症。在化疗或淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染引起的造血应激期间，活性 NLRP1a 导致长期的细胞减少症、骨髓发育不良和免疫抑制。相反，NLRP1 缺陷小鼠显示出从化疗和 LCMV 感染中恢复的增强，表明 NLRP1 作为细胞哨兵，提醒 Caspase-1 注意造血和感染应激。
