Neutrophils amplify inflammation in lupus through release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 alpha (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 demonstrate markedly increased IRE1α ribonuclease activity. Importantly, heightened IRE1α activity was also detected in neutrophils isolated from lupus patients, where it correlated with global disease activity. Immune complex-stimulated neutrophils produced both mitochondrial reactive oxygen species (mitoROS) and the activated form of caspase-2 in IRE1α-dependent fashion, while inhibition of IRE1α mitigated immune complex-mediated NETosis (both in human neutrophils and in a mouse model of lupus). Administration of an IRE1α inhibitor to lupus-prone MRL/lpr mice over eight weeks reduced mitochondrial ROS levels in peripheral blood neutrophils, while also restraining plasma-cell expansion and autoantibody formation. In summary, these data are the first to identify a role for IRE1α in the hyperactivity of lupus neutrophils, with this pathway apparently upstream of mitochondrial dysfunction, mitochondrial ROS formation, and NETosis. Inhibition of the IRE1α pathway appears to be a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions.
Gautam Sule, Basel H. Abuaita, Paul A. Steffes, Andrew T. Fernandes, Shanea K. Estes, Craig J. Dobry, Deepika Pandian, Johann E. Gudjonsson, J. Michelle Kahlenberg, Mary X. O'Riordan, Jason S. Knight