A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain

Hu, Xueming; Du, Lixia; Liu, Shenbin; Lan, Zhou; Zang, Kaikai; Feng, Jing; Zhao, Yue; Yang, Xingliang; Xie, Zili; Wang, Peter L.; Heul, Aaron M. Ver; Chen, Lvyi; Samineni, Vijay K.; Wang, Yanqing; Lavine, Kory J.; Gereau, Robert W.; Wu, Gregory F.; Hu, Hongzhen

doi:10.1172/jci161507

Cited by 36 publications

(27 citation statements)

References 62 publications

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“…We further tested whether genetic ablation of Hk2 in microglia affects neuropathic pain. Studies have shown that tamoxifen induction 4 weeks before the experiment allow the retention of Cre‐mediated effects in long‐living microglia, but not in peripheral monocytes and macrophages with rapid turnover (Figure 3a) (Ajami et al, 2007; Hu et al, 2023; Muller et al, 2010; Parkhurst et al, 2013; Peng et al, 2016). We used the same strategy to achieve selective ablation of Hk2 in microglia by TAM induction in Cx3cr1 creER/+ :: Hk2 fl/fl mice, 4 weeks before the SNI surgery.…”

Section: Resultsmentioning

confidence: 99%

HK2 in microglia and macrophages contribute to the development of neuropathic pain

Wang,

Jiang,

Cao

et al. 2023

Glia

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Neuropathic pain is a complex pain condition accompanied by prominent neuroinflammation involving activation of both central and peripheral immune cells. Metabolic switch to glycolysis is an important feature of activated immune cells. Hexokinase 2 (HK2), a key glycolytic enzyme enriched in microglia, has recently been shown important in regulating microglial functions. Whether and how HK2 is involved in neuropathic pain‐related neuroinflammation remains unknown. Using a HK2‐tdTomato reporter line, we found that HK2 was prominently elevated in spinal microglia. Pharmacological inhibition of HK2 effectively alleviated nerve injury‐induced acute mechanical pain. However, selective ablation of Hk2 in microglia reduced microgliosis in the spinal dorsal horn (SDH) with little analgesic effects. Further analyses showed that nerve injury also significantly induced HK2 expression in dorsal root ganglion (DRG) macrophages. Deletion of Hk2 in myeloid cells, including both DRG macrophages and spinal microglia, led to the alleviation of mechanical pain during the first week after injury, along with attenuated microgliosis in the ipsilateral SDH, macrophage proliferation in DRGs, and suppressed inflammatory responses in DRGs. These data suggest that HK2 plays an important role in regulating neuropathic pain‐related immune cell responses at acute phase and that HK2 contributes to neuropathic pain onset primarily through peripheral monocytes and DRG macrophages rather than spinal microglia.

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Section: Resultsmentioning

confidence: 99%

HK2 in microglia and macrophages contribute to the development of neuropathic pain

Wang,

Jiang,

Cao

et al. 2023

Glia

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Section: Central Inflammation Contributes To the Pathogenesis Of Chro...mentioning

confidence: 99%

“…154 TRPV4 expression in spinal resident microglia is increased in the mouse model of SNI, which transforms peripheral nerve injury into central sensitization and neuropathic pain through releasing lipocalin-2. 155 Astrocytes are more abundant (approximately 2-4 times) compared to microglia, and play crucial effects on controlling the extracellular microenvironment, repairing the imbalance of potassium, glutamate, and water homeostasis under normal physiological conditions. 156,157 Astrocytes are activated in various pathological conditions and convert to reactive states (also termed "astrogliosis") characterized by obvious morphological changes, a significant increase of GFAP, and a significant cellular proliferation, which is considered to be coupled with a loss of homeostatic functions of astrocytes.…”

Section: Pain Modulation By Central Glial Cellsmentioning

confidence: 99%

Inflammation in pathogenesis of chronic pain: Foe and friend

Fang,

Zhai,

Zhu

et al. 2023

Mol Pain

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Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

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“…11,44 These studies provide valuable insights into the contribution of LCN2 in pain signaling pathways and potential as a therapeutic target. 11 However, the effect of LCN2 on development of morphine tolerance and hyperalgesia remain unclear. Nonetheless, our immunofluorescence staining results conclusively illustrate that LCN2 is predominantly expressed in astrocytes subsequent to the development of morphine tolerance, with minimal to no expression observed in microglia.…”

Section: Pain Medicinementioning

confidence: 99%

Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord

Wang,

et al. 2023

Anesthesiology

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Background Endoplasmic reticulum (ER) stress plays a crucial role in the pathogenesis of neuroinflammation and chronic pain. Herein, we hypothesized that PRKR-like endoplasmic reticulum kinase (PERK) and Inositol-requiring enzyme type 1 (IRE1) regulate Lipocalin-2 (LCN2) and Nod-like receptor family pyrin domain containing 3 (NLRP3) expression in astrocytes, thereby contributing to morphine tolerance and hyperalgesia. Methods The study was performed in Sprague-Dawley rats and C57/Bl6 mice of both sexes. The expression of LCN2 and NLRP3 were assessed by Western blotting. The tail-flick, von Frey, and Hargreaves tests were used to evaluate nociceptive behaviors. Chromatin immunoprecipitation (ChIP) was conducted to analyze the binding of activating transcription factor 4 (ATF4) to the promoters of LCN2 and TXNIP. Whole-cell patch-clamp recordings were used to evaluate neuronal excitability. Results Pharmacological inhibition of the PERK and IRE1 attenuated the development of morphine tolerance and hyperalgesia in male [tail latency on day 7, 8.0 ± 1.13 s in the morphine + GSK2656157 (10 μg) group vs. 5.8 ± 0.65 s in the morphine group, P = 0.04, n = 6 rats per group] and female [tail latency on day 7, 6.0 ± 0.84 s in the morphine + GSK2656157 (10 μg) group vs. 3.1 ± 1.09 s in the morphine group, P = 0.0005, n = 6 rats per group] rats. Activation of PERK and IRE1 upregulated expression of LCN2 and NLRP3 in vivo and in vitro. ChIP analysis showed that ATF4 directly bound to the promoters of the LCN2 and TXNIP. LCN2 induced neuronal hyperexcitability in the spinal cord and dorsal root ganglia via melanocortin 4 receptor (MC4R). Conclusions Astrocyte ER stress sensors PERK and IRE1 facilitated morphine tolerance and hyperalgesia through upregulation of LCN2 and NLRP3 in the spinal cord.

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A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain

Cited by 36 publications

References 62 publications

HK2 in microglia and macrophages contribute to the development of neuropathic pain

HK2 in microglia and macrophages contribute to the development of neuropathic pain

Inflammation in pathogenesis of chronic pain: Foe and friend

Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord

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