Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization

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.

RETRACTED: Mechanisms of M2 Macrophage-Derived Exosomal Long Non-coding RNA PVT1 in Regulating Th17 Cell Response in Experimental Autoimmune Encephalomyelitisa

“…M2 macrophages are alternatively activated macrophages, and predominantly inhibit immune responses (7). Emerging evidence has revealed the beneficial roles of M2 macrophages in ameliorating EAE, and macrophages M2 polarization blocks EAE progression, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS (8). In light of this, we try to explore the underlying mechanism of M2 macrophages in Th17 cells balance in EAE.…”

Thymoma Associated Myasthenia Gravis (TAMG): Differential Expression of Functional Pathways in Relation to MG Status in Different Thymoma Histotypes

“…Apart from the above pathways related to neurodegeneration (Parkinson and Huntington disease) and metabolism (Oxidative phosphorylation) (bold/italics in Table 1), one of the eight identified MG-associated inflammatory pathways (9) showed the "counter-enrichment" pattern as well: The MacTh1 clusterassociated gene set was significantly upregulated in TAMGassociated B2 thymomas and downregulated in AB thymomas (bold/italics in Table 2). Imbalanced macrophage polarization is well-known to play an important role in T cell-and autoantibody-mediated autoimmune and allergic diseases (25)(26)(27)(28), and can affect T cell apoptosis (29), i.e., a key feature of normal thymic tolerance induction and abnormal thymopoiesis inside TAMG-associated thymomas (30). Furthermore, analyses of MHC class II expression levels and the step-wise maturation of thymocytes inside different thymoma subtypes already gave strong hints that the mechanisms shaping the autoimmune CD4+ T cell repertoire are different in AB and B2 thymomas (31).…”

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

“…The adenylyl cyclase activator Forskolin for example alleviates EAE motor disease by suppressing the expression of CD86 while enhancing M2 macrophage polarization at the site of inflammation [186] (Figure 1). Another example is the clinically approved immunomodulatory agent lenalidomide, which promotes M2 macrophage polarization to regulate CNS autoimmunity resulting in abolished progression of EAE [187].…”