Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization

Qinjie Weng,Fahmida Sattar,Liang Fang,Zijie Xu,Lijun Yang,Xuan Liu,Jiaying Wang,Zhikang Zhang,Jiahuan Zheng,Guifeng Hao,Jiajia Wang,Bo Yang,Mengting Zhao,Qiaojun He,Jing Wang,Q Richard Lu

doi:10.1038/s41419-018-0290-x

Abstract

Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide-treated IL10−/− BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS.

Highlights

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease, pathologically characterized by perivascular CD4+ T cells and monocytes inflammation, resulting in axonal demyelination and transection[1,2,3]
Recent studies have revealed that the balance between activation and polarization of M1 and M2 macrophages is important for the progression of EAE
We found that the upregulation of Arg[1] and Mrc[1] mRNA level induced by lenalidomide, about 27.3 and 6.7 times, is closer to that induced by IL13, while pomalidomide upregulated the mRNA level of Arg[1] and Mrc[1] only by 18.6 and 3.9 times, respectively (Supplementary Figure S1a, b)

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease, pathologically characterized by perivascular CD4+ T cells and monocytes inflammation, resulting in axonal demyelination and transection[1,2,3]. Current therapy of MS such as fingolimod, glatiramer acetate mainly depends on non-specific suppression of the. More effective pharmacological strategies for MS to reduce inflammation and diminish myelin damage in injured CNS is urgently needed. It has become clear that macrophages play a very important role in the pathogenesis of MS7. The function of macrophages in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS8, is often opposite[9]. M1 cells are classically activated macrophages, generally exhibit proinflammatory activity, whereas M2 cells are alternatively activated macrophages, predominantly inhibit immune responses[10]. M1 and M2 macrophages co-exist in vivo and present plastic

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Results

Conclusion