The IRE1α stress signaling axis is a key regulator of neutrophil antimicrobial effector function

Abstract

Activation of the endoplasmic reticulum stress sensor, IRE1, is required for effective immune responses against bacterial infection and is associated with human inflammatory diseases where neutrophils are a key immune component. However, the specific role of IRE1 in regulating neutrophil effector function has not been studied. Here we show that infection-induced IRE1 activation licenses neutrophil antimicrobial capacity, including IL-1{beta} production, NET formation, and MRSA killing. Inhibition of IRE1 diminished production of mitochondrial reactive oxygen species (mROS) and decreased CASPASE-2 activation, which both contributed to neutrophil antimicrobial activity. Mice deficient in Caspase-2 were highly susceptible to MRSA infection and failed to form NETs in a subcutaneous abscess. IRE1 activation enhanced calcium influx and citrullination of histone H3 (Cit-H3) independently of mROS production, suggesting that IRE1 coordinates multiple pathways required for NET formation. Our data demonstrate that the IRE1-Caspase-2 axis is a major driver of neutrophil activity against MRSA infection and highlight the importance of IRE1 in neutrophil antibacterial function.\n\nOne Sentence SummaryIRE1 controls neutrophil antimicrobial defenses