Pluto Bioinformatics

GSE131404: IRE1-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain

Bulk RNA sequencing

The IRE1-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1 or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1-XBP1 in leukocytes, or treated with pharmacological IRE1 inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain. SOURCE: Priyankara,J,Wickramasinghe (priyaw@wistar.org) - Genomics The Wistar Institute