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Papers of the Week


Papers: 27 Jul 2019 - 2 Aug 2019


Animal Studies


2019 07 19


Science


365


6450

Editor's Pick

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

Authors

Chopra S, Giovanelli P, Alvarado-Vazquez P A, Alonso S, Song M, Sandoval TA, Chae C-S, Tan C, Fonseca MM, Gutierrez S, Jimenez L, Subbaramaiah K, Iwawaki T, Kingsley PJ, Marnett LJ, Kossenkov AV, Crespo M S, Dannenberg AJ, Glimcher LH, Romero-Sandoval AE, et al.
Science. 2019 07 19; 365(6450).
PMID: 31320508.

Abstract

Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.