Activation of the integrated stress response in nociceptors drives methylglyoxal-induced pain

Barragán-Iglesias, Paulino; Kuhn, Jasper L.; Vidal‐Cantú, Guadalupe C.; Salinas-Abarca, Ana Belen; Granados‐Soto, Vinicio; Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.

doi:10.1097/j.pain.0000000000001387

Cited by 50 publications

(67 citation statements)

References 55 publications

(84 reference statements)

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“…This results in decreased cap-dependent translation and suppression of viral replication capability in host cells. Another upstream eIF2α kinase, PERK, is activated in DRG neurons in diabetic neuropathy (Inceoglu et al, 2015), an effect that is likely mediated by the toxic end glycation byproduct methylglyoxal (Barragan-Iglesias et al, 2019). We initially hypothesized that type I IFNs might induce eIF2α phosphorylation in DRG neurons via PKR activation given the well-established induction of this pathway in other cell types (Pindel and Sadler, 2011).…”

Section: Discussionmentioning

confidence: 99%

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

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Section: Discussionmentioning

confidence: 99%

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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“…Our finding that ISRIB attenuates bleomycin-and asbestos-induced fibrosis in young and old mice adds to a growing body of literature showing dramatic effects of ISRIB in age-related disease. A single dose of ISRIB has been shown to improve cognitive function in normal mice and in mice after traumatic brain injury (28,29,51), prevent neurodegeneration in murine prion disease (52), improve glucose tolerance and diabetes induced liver injury in rats (53), prevent postnatal hearing loss in a genetic mouse model (54), reduce neuropathic pain in a murine model of diabetic neuropathy (55), alleviate dwarfism in a murine model of chondrodysplasia (56), slow the growth of metastatic prostate cancer (57), improve survival of lymphoblast cell lines from patients with vanishing white matter disease (58), and alleviate the social deficit and elevated anxiety-like behavior in a murine model of these neuropsychiatric disorders (59). Interestingly, while ISRIB improved memory in normal animals, it did not do so in two murine models of Alzheimer's disease (60,61).…”

Section: Discussionmentioning

confidence: 99%

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

Watanabe

Markov

et al. 2020

Preprint

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Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to young mice was associated with increased recruitment of pathogenic monocyte-derived alveolar macrophages. Using genetic lineage tracing and transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased apoptosis and decreased recruitment of pathogenic monocyte-derived alveolar macrophages. These data support multicellular model of fibrosis involving epithelial cells, pathogenic monocyte-derived alveolar macrophages and fibroblasts.Inhibition of the integrated stress response in the aging lung epithelium ameliorates pulmonary fibrosis by preventing the prolonged recruitment of monocyte-derived alveolar macrophages.

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“…These observations demonstrate that MS pathology extends beyond the CNS into the PNS. Several recent reports have implicated ER stress in mediating pain hypersensitivity in various models of neuropathy, including diabetic neuropathy (18,20,36), spinal nerve ligation (24,37), vasculitic peripheral neuropathy (22) and CFA-induced orofacial neuropathy (38).…”

Section: Discussionmentioning

confidence: 99%

“…The ISR has previously been implicated in pain pathophysiology (19,36) as well as EAE (45,46). The ISR pathway involves the phosphorylation of eIF2α by an assortment of kinases -PERK, protein kinase R (PKR), heme-regulated eIF2α kinase (HRI), and general control nonderepressible 2 kinase (GCN2) -each of which is initiated by a variety of stressors (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of eIF2α allows the cell to rapidly respond to a stressor by reducing translation of certain genes and increasing translation of others, especially genes with upstream open reading frame (uORF) including, but not limited to, ATF4 and CHOP. Selective translation of genes that may enhance the excitability of sensory neurons in the context of pain, particularly IB4+ nociceptors, has recently been reported (36). ISR inhibitor (ISRIB) is a commonly used compound to suppress the effects of p-eIF2α without altering its levels (49) however the initiating stressors (e.g.…”

Section: Discussionmentioning

confidence: 99%

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ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

Yousuf¹,

Samtleben²,

Lamothe

et al. 2020

Preprint

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AcknowledgementsWe would like to thank Drs. Simonetta Sipione, Christine Webber, and Jason Plemel (University of Alberta) for graciously sharing select equipment and software. ABSTRACTNeuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca 2+ transients in putative DRG nociceptors. We went to assess disease-mediated changes in the functional properties of Ca 2+ -sensitive BK-type K + channels in DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

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Activation of the integrated stress response in nociceptors drives methylglyoxal-induced pain

Cited by 50 publications

References 55 publications

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

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