Abstract

BackgroundSpinal cord microglia plays a crucial role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely determined. Here, we investigated the role of Pellino1 (Peli1) and its interplay with spinal microglial activation in neuropathic pain.MethodsIn this study, we examined the effects of Peli1 on pain hypersensitivity and spinal microglial activation after chronic constriction injury (CCI) of the sciatic nerve in mice. The molecular mechanisms involved in Peli1-mediated hyperalgesia were determined by western blot, immunofluorescence, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). We utilized immunoprecipitation to examine the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) following CCI. In addition, we explored the effect of Peli1 on BV2 microglial cells in response to lipopolysaccharide (LPS) challenge.ResultsWe found that CCI induced a significant increase in the levels of Peli1, which was present in the great majority of microglia in the spinal dorsal horn. Our results showed that spinal Peli1 contributed to the induction and maintenance of CCI-induced neuropathic pain. The biochemical data revealed that CCI-induced Peli1 in the spinal cord significantly increased mitogen-activated protein kinase (MAPK) phosphorylation, activated nuclear factor kappa B (NF-κB), and enhanced the production of proinflammatory cytokines, accompanied by spinal microglial activation. Peli1 additionally was able to promote K63-linked ubiquitination of TRAF6 in the ipsilateral spinal cord following CCI. Furthermore, we demonstrated that Peli1 in microglial cells significantly enhanced inflammatory reactions after LPS treatment.ConclusionThese results suggest that the upregulation of spinal Peli1 is essential for the pathogenesis of neuropathic pain via Peli1-dependent mobilization of spinal cord microglia, activation of MAPK/NF-κB signaling, and production of proinflammatory cytokines. Modulation of Peli1 may serve as a potential approach for the treatment of neuropathic pain.

Highlights

  • Neuropathic pain is triggered by the damage to the peripheral nerve or central nervous system and characterized by increased sensitivity to innocuous and noxious stimulation [1,2,3]

  • Peli1 is increased in spinal cord after constriction injury (CCI) To explore the potential role of Peli1 in neuropathic pain, we examined Peli1 expression in the ipsilateral spinal cord at segments L4-L5 on day 3, 7, and 14 following CCI

  • We further evaluated microglial markers Ionized calcium binding adaptor molecule 1 (Iba1) and Cluster of differentiation 11b (CD11b) mRNA expression in the ipsilateral spinal cord. quantitative polymerase chain reaction (qPCR) results showed that CCI robustly upregulated the levels of Iba1 and CD11b

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Summary

Introduction

Neuropathic pain is triggered by the damage to the peripheral nerve or central nervous system and characterized by increased sensitivity to innocuous and noxious stimulation [1,2,3]. Numerous studies have demonstrated that microglial cells in the spinal cord play a vital role in the pathogenesis of neuropathic pain [3,4,5,6,7]. After nerve damage, the upregulation of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β) released from activated microglial cells are involved in the sensitization of neurons via microglia-neuron interaction in the spinal cord [14, 15]. Activation of p38 MAPK in spinal cord microglia, but not in neurons and astrocytes, contributes to neuropathic pain via the induction of proinflammatory cytokines [16, 17]. Spinal cord microglia plays a crucial role in the pathogenesis of neuropathic pain. We investigated the role of Pellino (Peli1) and its interplay with spinal microglial activation in neuropathic pain

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