Genetic and pharmacological targeting of GSDMD ameliorates systemic inflammation in macrophage activation syndrome.
Genetic and pharmacological targeting of GSDMD ameliorates systemic inflammation in macrophage activation syndrome.
复制标题
DOI：
10.1016/j.jaut.2022.102929
复制
发表时间：
2022-10
影响因子：
12.8
通讯作者：
Shunli Tang;Changyi Yang;Sheng Li;Yuwei Ding;Ding-xian Zhu;Shuni Ying;Chuanyin Sun;Yuzhu Shi;J. Qiao;H. Fang
中科院分区：
文献类型：
--
作者：
Shunli Tang;Changyi Yang;Sheng Li;Yuwei Ding;Ding-xian Zhu;Shuni Ying;Chuanyin Sun;Yuzhu Shi;J. Qiao;H. Fang
巨噬细胞激活综合征(MAS)是自身免疫/自身炎症性疾病的一种潜在的危及生命的并发症，其特征是巨噬细胞和细胞毒性T淋巴细胞在多个器官中过度扩张和激活。最常见的是，MAS发生在系统性幼年特发性关节炎患者和相当于成人的成人起病斯蒂尔病(AOSD)中。Gasdermin D(GSDMD)是一种关键的成孔效应蛋白，通过释放其N端片段形成跨膜孔，介导促炎细胞因子的分泌。GSDMD与多种炎症性疾病有关，但其在MAS中的作用尚不清楚。在这里，我们揭示了与健康对照组相比，AOSD患者血清GSDMD-N水平升高。此外，AOSD患者MAS特征的出现导致了进一步的升高。血清GSDMD水平与血清铁蛋白、白介素18水平呈正相关。用未甲基化的胞嘧啶-磷酸-鸟嘌呤(CpG)反复刺激Toll样受体9可引起野生型小鼠的MAS症状，包括体重减轻、全血细胞减少和肝脾肿大。GSDMD的基因缺失和药理作用抑制改善了小鼠的MAS症状，同时减少了脾和肝巨噬细胞的浸润和IL-18的产生。与活体结果一致的是，从GSDMD−/−小鼠获得的骨髓来源的巨噬细胞或经GSDMD抑制剂双硫兰处理的骨髓来源的巨噬细胞在CpG刺激后IL-18的表达减弱。总而言之，我们的发现确定GSDMD是MAS并发症的新标记物和MAS治疗的有前景的靶点。
Macrophage activation syndrome (MAS), a potentially life-threatening complication of autoimmune/autoinflammatory diseases, is characterized by the excessive expansion and activation of macrophages and cytotoxic T lymphocytes in multiple organs. Most commonly, MAS occurs in patients with systemic juvenile idiopathic arthritis and in its adult equivalent, adult-onset Still's disease (AOSD). Gasdermin D (GSDMD) is a critical pore-forming effector protein that mediates pro-inflammatory cytokine secretion via releasing its N terminal fragments to form transmembrane pores. GSDMD has been implicated in various inflammatory diseases, however, its role in MAS remains elusive. Here, we unveiled that the serum levels of GSDMD-N were elevated in patients with AOSD compared to heathy controls. In addition, the emergence of MAS features in AOSD patients resulted in further elevation. The serum levels of GSDMD were positively correlated with ferritin and interleukin-18 (IL-18). Repeated toll-like receptor 9 stimulation with unmethylated cytosine-phosphate-guanine (CpG) induced MAS symptoms in wild-type mice, including body weight loss, pancytopenia and hepatosplenomegaly. Genetic deletion and pharmacological inhibition of GSDMD ameliorated MAS symptoms in mice with the concomitant reduction of splenic and hepatic macrophage infiltration and IL-18 production. Consistent with thesein vivoresults, bone marrow-derived macrophages obtained from GSDMD−/−mice or treated with GSDMD inhibitor disulfiram exhibited attenuated IL-18 expression after CpG stimulation. Collectively, our findings identified GSDMD as a novel marker for MAS complication and a promising target for MAS treatment.