期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 7, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI137866
关键词
-
资金
- Target Identification in Lupus grant from the Lupus Research Alliance
- NIH [R01AR071384, R01AI130025, R21AI13540, R01HL134846, P30AR075043]
- Career Development Award from the Burroughs Wellcome Fund
- Postdoctoral Translational Scholars Program fellowship award from the National Center for Advancing Translational Sciences of the NIH [2UL1TR000433]
- Taubman Medical Research Institute Innovation Program
The study reveals a role for IRE1 alpha in the hyperactivity of lupus neutrophils, with its inhibition potentially mitigating disease activity and reducing mitochondrial ROS levels. This suggests that targeting NETosis through the IRE1 alpha pathway could be a novel strategy for neutralizing inflammation in lupus.
Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 alpha (IRE1 alpha) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1 alpha 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 IRE1 alpha ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1 alpha 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 IRE1 alpha-dependent fashion, whereas inhibition of IRE1 alpha mitigated immune complex-mediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1 alpha 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 IRE1 alpha 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 IRE1 alpha pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据