Sule Gautam, Abuaita Basel H, Steffes Paul A, Fernandes Andrew T, Estes Shanea K, Dobry Craig, Pandian Deepika, Gudjonsson Johann E, Kahlenberg J Michelle, O'Riordan Mary X, Knight Jason S
Division of Rheumatology, Department of Internal Medicine.
Department of Microbiology and Immunology, and.
J Clin Invest. 2021 Apr 1;131(7). doi: 10.1172/JCI137866.
Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 α (IRE1α) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1α has been little studied in relation to neutrophil function or lupus pathogenesis. Here, we found that neutrophils activated by lupus-derived immune complexes demonstrated markedly increased IRE1α ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1α activity that was correlated with global disease activity. Immune complex-stimulated neutrophils produced both mitochondrial ROS (mitoROS) and the activated form of caspase-2 in an IRE1α-dependent fashion, whereas inhibition of IRE1α mitigated immune complex-mediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1α inhibitor to lupus-prone MRL/lpr mice over 8 weeks reduced mitoROS levels in peripheral blood neutrophils, while also restraining plasma cell expansion and autoantibody formation. In summary, these data identify a role for IRE1α in the hyperactivity of lupus neutrophils and show that this pathway is upstream of mitochondrial dysfunction, mitoROS formation, and NETosis. We believe that inhibition of the IRE1α pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions.
中性粒细胞通过释放中性粒细胞胞外诱捕网（NETs）加剧狼疮中的炎症反应。内质网应激传感器肌醇需求酶1α（IRE1α）被认为是多种慢性疾病中炎症的持续推动者；然而，关于IRE1α与中性粒细胞功能或狼疮发病机制的关系，此前研究甚少。在此，我们发现狼疮来源的免疫复合物激活的中性粒细胞表现出显著增加的IRE1α核糖核酸酶活性。重要的是，在从狼疮患者分离出的中性粒细胞中，我们也检测到IRE1α活性增强，且其与整体疾病活动相关。免疫复合物刺激的中性粒细胞以IRE1α依赖的方式产生线粒体活性氧（mitoROS）和活化形式的半胱天冬酶-2，而抑制IRE1α可减轻免疫复合物介导的NETosis（在人中性粒细胞和狼疮小鼠模型中均如此）。对易患狼疮的MRL/lpr小鼠连续8周给予IRE1α抑制剂，可降低外周血中性粒细胞中的mitoROS水平，同时还能抑制浆细胞扩增和自身抗体形成。总之，这些数据确定了IRE1α在狼疮中性粒细胞过度活化中的作用，并表明该途径在线粒体功能障碍、mitoROS形成和NETosis的上游。我们认为抑制IRE1α途径是中和狼疮及潜在其他炎症性疾病中NETosis的一种新策略。
