IRE1α–XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain

A “sUPR” target for pain management? The unfolded protein response (UPR) is initiated when unfolded or misfolded proteins accumulate in the endoplasmic reticulum. One highly conserved arm of the UPR, the IRE1α–XBP1 signaling pathway, also plays a role in various other UPR-independent processes, including hypoxia, angiogenesis, and inflammation. Chopra et al. report that this pathway additionally regulates the production of two molecules, cyclooxygenase 2 and microsomal prostaglandin E synthase 1, that help mediate inflammation-induced pain (see the Perspective by Avril and Chevet). When elements of the IRE1α–XBP1 signaling pathway were knocked out, pain behaviors were reduced in two different mouse models of pain. Targeting this pathway may result in improved pain management therapies. Science, this issue p. eaau6499; see also p. 224 An endoplasmic reticulum stress sensor modulates immune-mediated pain. INTRODUCTION Tissue injury triggers rapid local responses coordinated by immune cells, which dictate the maintenance and resolution of inflammation and therefore the recovery from functional impairment and pain. This inflammatory process requires high levels of protein synthesis, folding, modification, and trafficking, which are events regulated by the endoplasmic reticulum (ER). Excessive protein synthesis and handling can lead to the accumulation of misfolded proteins in this organelle, provoking a cellular state of “ER stress” and subsequent activation of the unfolded protein response (UPR). The IRE1α–XBP1 signaling pathway is an evolutionarily conserved branch of the UPR that maintains ER homeostasis while simultaneously governing various immunometabolic processes. Yet, the physiological consequences of IRE1α–XBP1 signaling in leukocytes during tissue injury and inflammation remain largely unexplored. RATIONALE IRE1α–XBP1 signaling mediates the rapid induction of pro-inflammatory cytokines in myeloid cells. This pathway has also been implicated in the regulation of lipid metabolic processes that are central for programming immune cell functions in health and disease. Nonetheless, whether IRE1α–XBP1 activation in leukocytes modulates the pain that can be driven by inflammatory processes has not been studied. The scarcity of pharmaceutical products that effectively manage postoperative pain has promoted the use of opioids, in turn contributing to the opioid crisis in the United States. Identifying the key molecular pathways that endow immune cells with potent pro-algesic attributes may lead to the development of more effective and safer strategies for pain treatment. We examined whether leukocyte-intrinsic IRE1α–XBP1 signaling controls transcriptional and metabolic programs that could be implicated in inflammation and pain development. RESULTS Transcriptomic analyses of mouse bone marrow–derived dendritic cells stimulated by pattern recognition receptors revealed that IRE1α was necessary for the optimal expression of gene networks involved in eicosanoid metabolism. IRE1α deficiency blunted the normal induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) in stimulated myeloid cells. This in turn reduced the capacity of myeloid cells to produce multiple prostaglandins, including the pro-algesic lipid mediator PGE2. We determined that upon activation by IRE1α, the functional form of transcription factor XBP1 bound to the human PTGS2 and PTGES genes to directly induce their expression and enable robust PGE2 generation. Selective loss of IRE1α or XBP1 in leukocytes decreased PGE2 biosynthesis in vivo upon challenge with pro-inflammatory stimuli and reduced pain-related behaviors in PGE2-dependent models of visceral and postsurgical pain. Blocking IRE1α activation by using small-molecule inhibitors evoked similar antinociceptive effects in both models of pain evaluated. CONCLUSIONS Our study demonstrates that the IRE1α–XBP1 arm of the UPR operates as a crucial mediator of eicosanoid metabolism and prostaglandin synthesis in myeloid immune cells by promoting the expression of both Cox-2 and mPGES-1. We determined that abrogating this pathway genetically or pharmacologically diminishes pain-related behaviors in mice. Modulating IRE1α–XBP1 signaling may be helpful to induce better analgesia with the goal of improved pain management and reduced opioid use. Activation of the IRE1α–XBP1 pathway in leukocytes promotes PGE2 generation and pain. ER stress, inflammatory conditions, or engagement of pattern recognition receptors, such as Toll-like receptors (TLRs), trigger IRE1α activation and generation of functional XBP1 in myeloid leukocytes. This multitasking transcription factor induces the expression of both Cox-2 and mPGES-1, which are enzymes that catalyze the synthesis of PGE2 from arachidonic acid. PGE2 is known to function as a potent lipid mediator that promotes pain by activating and sensitizing nociceptors. Disabling IRE1α–XBP1 signaling reduces behavioral pain responses in PGE2-dependent mouse models of postsurgical and inflammatory visceral pain. 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.