2. Academic Validation
  3. IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain

  • Science. 2019 Jul 19;365(6450):eaau6499. doi: 10.1126/science.aau6499.
Sahil Chopra  # 1 2 3,  Paolo Giovanelli 1 2 3,  Perla Abigail Alvarado-Vazquez 4,  Sara Alonso 5,  Minkyung Song 2 3,  Tito A Sandoval 2 3,  Chang-Suk Chae 2 3,  Chen Tan 2 3,  Miriam M Fonseca 4,  Silvia Gutierrez 4,  Leandro Jimenez 6 7,  Kotha Subbaramaiah 8,  Takao Iwawaki 9,  Philip J Kingsley 10,  Lawrence J Marnett 10 11,  Andrew V Kossenkov 12,  Mariano Sanchez Crespo 5,  Andrew J Dannenberg 8,  Laurie H Glimcher 13 14,  E Alfonso Romero-Sandoval 15,  Juan R Cubillos-Ruiz  # 16 2 3
Affiliations

Affiliations

  • 1 Weill Cornell Graduate School of Medical Sciences, Cornell University. New York, NY 10065, USA.
  • 2 Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA.
  • 3 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • 4 Department of Anesthesiology, Pain Mechanisms Laboratory, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
  • 5 Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain.
  • 6 Instituto Ludwig de Pesquisa Sobre o Câncer, São Paulo, Brazil.
  • 7 Hospital Sírio-Libanês, São Paulo, Brazil.
  • 8 Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 9 Division of Cell Medicine, Medical Research Institute, Kazanawa Medical University, Ishikawa, Japan.
  • 10 Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 11 A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
  • 12 Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 13 Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. laurie_glimcher@dfci.harvard.edu eromeros@wakehealth.edu jur2016@med.cornell.edu.
  • 14 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 15 Department of Anesthesiology, Pain Mechanisms Laboratory, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. laurie_glimcher@dfci.harvard.edu eromeros@wakehealth.edu jur2016@med.cornell.edu.
  • 16 Weill Cornell Graduate School of Medical Sciences, Cornell University. New York, NY 10065, USA. laurie_glimcher@dfci.harvard.edu eromeros@wakehealth.edu jur2016@med.cornell.edu.
  • # Contributed equally.
PMID: 31320508 DOI: 10.1126/science.aau6499
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 (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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