PT  - JOURNAL ARTICLE
AU  - B. H. Abuaita
AU  - G. J. Sule
AU  - T. L. Schultz
AU  - F. Gao
AU  - J. S. Knight
AU  - M. X. O’Riordan
TI  - The IRE1α stress signaling axis is a key regulator of neutrophil antimicrobial effector function
AID  - 10.1101/743336
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 743336
4099  - http://biorxiv.org/content/early/2019/08/22/743336.short
4100  - http://biorxiv.org/content/early/2019/08/22/743336.full
AB  - Activation of the endoplasmic reticulum stress sensor, IRE1α, 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 IRE1α in regulating neutrophil effector function has not been studied. Here we show that infection-induced IRE1α activation licenses neutrophil antimicrobial capacity, including IL-1β production, NET formation, and MRSA killing. Inhibition of IRE1α 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. IRE1α activation enhanced calcium influx and citrullination of histone H3 (Cit-H3) independently of mROS production, suggesting that IRE1α coordinates multiple pathways required for NET formation. Our data demonstrate that the IRE1α-Caspase-2 axis is a major driver of neutrophil activity against MRSA infection and highlight the importance of IRE1α in neutrophil antibacterial function.One Sentence Summary IRE1α controls neutrophil antimicrobial defenses