Abstract

Multiple sclerosis (MS) is a potentially disabling disease of the central nervous system. Approximately half of the patients with MS experience severe pain; however, currently available therapeutics provide only insufficient relief. The mechanisms underlying the generation of neuropathic pain in patients with MS are not fully understood. Recently, we found that neutrophil elastase from accumulated neutrophils in the dorsal root ganglion (DRG) sensitizes DRG neurons and induces mechanical allodynia in a mouse model of experimental autoimmune encephalomyelitis (EAE). However, the mechanism underlying neutrophil accumulation in the DRG after myelin oligodendrocyte glycoprotein (MOG35–55, immunogenic peptide) immunization remains unclear. Here, we found that C-X-C motif ligand 1 (CXCL1) was upregulated in DRG neurons after MOG35–55 immunization. Increased expression of CXCL1 protein was also observed in primary cultured DRG neurons treated with MOG35–55, which was mediated through toll-like receptor 4 (TLR4). Gene silencing of TLR4 or CXCL1 in DRG neurons significantly attenuated neutrophil accumulation in the DRG and mechanical allodynia during the preclinical phase of EAE (around day 5 after immunization). Our results thus suggest that a TLR4–CXCL1 pathway in DRG neurons triggers neutrophil recruitment in the DRG and subsequent mechanical allodynia in response to MOG35–55.

Highlights

  • Multiple sclerosis (MS) is a progressive inflammatory disease that manifests as neurological deficits including motor, cognitive, and neuropsychiatric symptoms

  • Immunohistochemical analysis found that intensity of C-X-C motif ligand 1 (CXCL1) immunofluorescence, which was merged with Nissl fluorescence, in the dorsal root ganglion (DRG) slices was significantly increased at 5 days after MOG35–55 immunization (Fig. 1e)

  • These results suggest that increased expression of CXCL1 in DRG neurons is synchronized with neutrophil accumulation in the DRG after MOG35–55 immunization

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Summary

Introduction

Multiple sclerosis (MS) is a progressive inflammatory disease that manifests as neurological deficits including motor, cognitive, and neuropsychiatric symptoms. It has been observed that mechanical allodynia caused by MOG35–55 immunization starts prior to the activation of non-neuronal cells in the SDH3,5,6. We previously found that the activation of neutrophils is synchronized with the induction of mechanical allodynia in MOG35–55-immunized mice These cells accumulate in the dorsal root ganglion (DRG), which is a cluster of neurons in a posterior root of a spinal nerve that carries sensory information, but not in the central nervous system (CNS) including the spinal cord and brainstem. The aim of this study was to elucidate whether an increment in CXCL1 protein levels in the DRG contributes to neutrophil accumulation and induces mechanical allodynia in MOG35–55-immunized mice

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