Leonurine suppresses neuroinflammation through promoting oligodendrocyte maturation.

Min Jin,Bing Wan,Yuting Gu,Jiefang Huang,Qian Li,Xuanbai Xu,Yanyun Zhang,Rui Huang

doi:10.1111/jcmm.14053

Abstract

Focal inflammation and remyelination failure are major hallmarks of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we found that leonurine, a bioactive alkaloid, alleviated EAE disease severity along with reduced central nervous system inflammation and myelin damage. During the pathogenesis of EAE, leonurine dramatically suppressed the recruitment of encephalitogenic T cells into the central nervous system, whereas did not impair periphery immune responses and microglia activation. Mechanistically, leonurine protected mice against demyelination along with enhanced remyelination through promoting the maturation of oligodendrocytes in both EAE and cuprizone‐induced demyelination mouse models. Moreover, we identified that the expression of demethylase jumonji domain‐containing protein D3 was significantly enhanced upon treatment of leonurine, which suppressed the trimethylation of histone H3 lysine‐27 and enhanced oligodendrocyte maturation accordingly. Collectively, our study identified the therapeutic effect of leonurine on EAE model, which potentially represents a promising therapeutic strategy for multiple sclerosis, even other demyelination disorders.

Highlights

Multiple sclerosis (MS) is an autoimmune disease, characterized by central nervous system (CNS) inflammation, demyelination, axonal loss, and degeneration.[1,2] Myelin peptide MOG35-55‐induced experimental autoimmune encephalomyelitis (EAE), which recapitulatesMin Jin and Qian Li contributed to this work.CNS inflammation and demyelination, is a widely used autoimmune disease animal model for human MS.[3,4] Demyelination in EAE is mediated by peripheral preactivated, autoreactive, and myelin‐specific T cells that migrate and infiltrate into the CNS, where they become reactivated by antigen‐presenting cells and produce inflammatory cytokines, such as interleukins (e.g. IL‐1β, IL‐6, and IL‐17), tumour necrosis factor‐α, and interferon‐γ (IFN‐γ)
We provided several lines of evidence that leonurine alleviated disease severity of EAE by promoting OL differentiation, which conferred reduced encephalitogenic T cells
We found that leonurine had no effect on T cell response in the periphery, indicating by similar components of CD4+ and CD8+ T cells in the draining lymph node (DLN) of vehicle‐ and leonurine‐treated EAE mice, as well as similar proliferation, cytokine profile, and ability to induce EAE of MOG35-55 challenged T cells from vehicle‐ and leonurine‐treated EAE mice

Summary

| INTRODUCTION

Multiple sclerosis (MS) is an autoimmune disease, characterized by central nervous system (CNS) inflammation, demyelination, axonal loss, and degeneration.[1,2] Myelin peptide MOG35-55‐induced experimental autoimmune encephalomyelitis (EAE), which recapitulates. Song et al showed that leonurine inhibited cyclooxygenase‐2 expression in lipopolysaccharide‐ induced mouse mastitis.[15] Li et al demonstrated that leonurine attenuated fibroblast‐like synoviocyte‐mediated synovial inflammation and joint destruction in rheumatoid arthritis.[16] More recently, leonurine reportedly could decrease microglia or macrophage overactivation in Alzheimer's disease and monosodium urate crystal‐induced inflammation.[17,18] Besides, leonurine was surprisingly found exhibiting neuroprotective function in neurodegenerative diseases, such as Parkinson's disease,[19] stroke,[20,21] and Alzheimer's disease,[17] protecting brain from ischaemic injury and reducing neuron loss In view of these findings, we set out to examine a possible role of leonurine in the CNS autoimmune disease EAE. Our study demonstrates leonurine as a potential therapeutic compound for CNS autoimmune diseases

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION