A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.

Yasunobu Arima,Tadafumi Kawamoto,Peter Wieghofer,Daisuke Kamimura,Saburo Sakoda,Marco Prinz,Issei Komuro,Masaaki Murakami,Shizuya Saika,Yoshichika Yoshioka,Toru Atsumi,Yuji Morimoto,Masaya Harada,Naoki Nishikawa,Toshio Hirano,Andrea Štofková ,Yoshinori Okada ,Yutaka Mori ,Takao Ohki ,Toshio Yamashita ,Kazutoshi Higuchi

doi:10.7554/elife.08733

Abstract

Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.

Highlights

Multiple sclerosis (MS) is genetically a T helper cell (CD4+ T cell)-mediated autoimmune disease (International Multiple Sclerosis Genetics Consortium et al, 2011) that is characterized by chronicArima et al eLife 2015;4:e08733
Quantification of the histological analysis around the ventral vessels based on MFI in dotted circles and cell number of the accumulated MHC class II+ cells in dotted circles by using serial frozen sections stained with anti-MHC class II antibody and Hoechst. (D) EAE development was evaluated with clodronate liposome administration into the cisterna magna (CM) or the peritoneal cavity day 21 after pathogenic T cell transfer in the presence of pain induction in EAE-recovered mice (n = 3–5 per group)
Quantification of the histological analysis around the ventral vessels based on MFI in dotted circles and cell number of the accumulated MHC class II+ cells in dotted circles by using serial frozen sections stained with anti-MHC class II antibody and Hoechst. (F) Immunohistochemical staining for cfos in the somatosensory area of EAE-recovered mice with L-Homocysteic acid administration to the somatosensory area (n = 3 per group)

Summary

Introduction

Multiple sclerosis (MS) is genetically a T helper cell (CD4+ T cell)-mediated autoimmune disease (International Multiple Sclerosis Genetics Consortium et al, 2011) that is characterized by chronic. The experiments showed that a painful sensation could trigger a relapse in the mice via the so-called ‘gateway reflex’. This reflex describes the phenomenon whereby nerve impulses lead to the release of signaling molecules that cause the walls of nearby blood vessels to open and allow immune cells to move from the bloodstream to the central nervous system. This in turn stimulates the development of inflammation, which causes an imbalance in the affected sites of the central nervous system

Methods

Results

Conclusion