Center for Inflammation Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium.
Department of Internal Medicine, Ghent University, Ghent, Belgium.
J Exp Med. 2018 Jun 4;215(6):1519-1529. doi: 10.1084/jem.20172060. Epub 2018 May 23.
Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that infection of FMF knock-in macrophages that express a chimeric FMF-associated Pyrin elicited pyroptosis and gasdermin D (GSDMD)-mediated interleukin (IL)-1β secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1β-dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.
细胞焦亡是一种由炎症小体诱导的裂解性细胞死亡方式，其在慢性炎症性疾病中的生理作用尚不清楚。家族性地中海热（FMF）是世界上最常见的单基因自身炎症性疾病，估计有 15 万名患者受到影响。该病是由 上的错义突变引起的，这些突变激活了 Pyrin 炎症小体，但 FMF 中自身炎症的病理生理机制尚不完全清楚。在这里，我们表明，表达嵌合 FMF 相关 Pyrin 的 FMF 基因敲入巨噬细胞感染 可引发细胞焦亡和 gasdermin D（GSDMD）介导的白细胞介素（IL）-1β分泌。重要的是，体内 GSDMD 缺失可消除自发性自身炎症性疾病。GSDMD 缺陷型 FMF 基因敲入小鼠完全免受该自身炎症性疾病模型的生长迟缓、贫血、全身炎症细胞因子产生、中性粒细胞增多和组织损伤的影响。总的来说，这项工作确定了细胞焦亡是 FMF 中依赖于 IL-1β 的自身炎症的一个关键机制，并强调了 GSDMD 抑制作为炎症小体驱动的疾病的一种潜在抗炎策略。
