| First Author | Sule G | Year | 2021 |
| Journal | J Clin Invest | Volume | 131 |
| Issue | 7 | PubMed ID | 33561013 |
| Mgi Jnum | J:339590 | Mgi Id | MGI:6709823 |
| Doi | 10.1172/JCI137866 | Citation | Sule G, et al. (2021) Endoplasmic reticulum stress sensor IRE1alpha propels neutrophil hyperactivity in lupus. J Clin Invest 131(7) |
| abstractText | Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 alpha (IRE1alpha) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1alpha 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 IRE1alpha ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1alpha 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 IRE1alpha-dependent fashion, whereas inhibition of IRE1alpha mitigated immune complex-mediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1alpha 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 IRE1alpha 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 IRE1alpha pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions. |
