TY - JOUR
T1 - IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain
AU - Chopra, Sahil
AU - Giovanelli, Paolo
AU - Alvarado-Vazquez, Perla Abigail
AU - Alonso, Sara
AU - Song, Minkyung
AU - Sandoval, Tito A.
AU - Chae, Chang Suk
AU - Tan, Chen
AU - Fonseca, Miriam M.
AU - Gutierrez, Silvia
AU - Jimenez, Leandro
AU - Subbaramaiah, Kotha
AU - Iwawaki, Takao
AU - Kingsley, Philip J.
AU - Marnett, Lawrence J.
AU - Kossenkov, Andrew V.
AU - Crespo, Mariano Sanchez
AU - Dannenberg, Andrew J.
AU - Glimcher, Laurie H.
AU - Romero-Sandoval, E. Alfonso
AU - Cubillos-Ruiz, Juan R.
N1 - Funding Information:
Our research was supported by the Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense (J.R.C.-R.), The Pershing Square Sohn Cancer Research Alliance (J.R.C.-R.), Weill Cornell Medicine Funds (J.R.C.-R. and L.H.G.), Department of Anesthesiology-Wake Forest School of Medicine Funds (E.A.R.-S.), NIH grant R01CA112663 (L.H.G.), Plan Nacional de Salud y Farmacia Grant SAF2017-83079-R (M.S.C.), and NIH grant 1S10OD017997-01A1 (L.J.M.).
Publisher Copyright:
© 2019 American Association for the Advancement of Science. All rights reserved.
PY - 2019/7/19
Y1 - 2019/7/19
N2 - Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signalingmaintains 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 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/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 (PGE2), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE2 production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE2-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
AB - Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signalingmaintains 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 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/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 (PGE2), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE2 production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE2-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
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U2 - 10.1126/science.aau6499
DO - 10.1126/science.aau6499
M3 - Article
C2 - 31320508
AN - SCOPUS:85070059028
SN - 0036-8075
VL - 365
JO - Science
JF - Science
IS - 6450
M1 - eaau6499
ER -