Research Article: p38MAPK/SGK1 signaling regulates macrophage polarization in experimental autoimmune encephalomyelitis

Date Published: February 15, 2019

Publisher: Impact Journals

Author(s): Bo Li, Tian-Bi Tan, Liang Wang, Xiao-Yun Zhao, Guo-Jun Tan.

http://doi.org/10.18632/aging.101786

Abstract

Multiple sclerosis (MS) is characterized with multifocal demyelination resulting from activation and infiltration of inflammatory cells into the central nerve system. Recent reports suggest that p38 mitogen-activated protein kinase (MAPK) / serum- and glucocorticoid-inducible protein kinase 1 (SGK1) signaling pathway contributes to the pathology of MS through regulation of immunity. However, the role of this signaling pathway in MS-related macrophage activation and polarization has not been studied. Here, we used an experimental autoimmune encephalomyelitis (EAE) model for MS to study the role of p38MAPK/SGK1 signaling in the macrophage polarization and its effects on the development and severity of EAE. Here, we found that p38MAPK/SGK1 signaling is required for IL4-induced M2 macrophage polarization in vitro. Chitin-induced M2 macrophage polarization reduces the severity of EAE in mice. Generation of an adeno-associated virus (AAV) carrying sh-p38 or sh-SGK1 under the control of a CD68 promoter successfully knockdown p38 or SGK1 levels in vitro and in vivo. Treatment with AAV-sh-p38 or AAV-sh-SGK1 abolished the effects of Chitin on macrophage polarization and the severity of EAE. Thus, our data suggest that p38MAPK/SGK1 signaling induces M2 macrophage polarization, which reduces the severity of EAE, a model for MS.

Partial Text

Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS), characterized with a specific neurological disorder called multifocal demyelination resulting from activation and infiltration of inflammatory cells into the CNS [1]. The most important inflammatory cells that participate into the initiation, progression and development of MS are antigen-specific T cells (Th1 and Th17 cells appear to be the critical ones) and macrophages [2]. Although the T cells have been extensively studies for their role and functions in the pathogenesis of MS, the exact role and functions of macrophages remain poorly understood.

MS is a chronic autoimmune inflammatory CNS disease that affects approximately 1 million people worldwide [2]. Pathogenic T cells recognize myelin antigens in the CNS lead to focal demyelination, loss of axons, and gliosis. While CD4 T cells initiate the inflammatory cascade in the CNS, other immune and resident cells, including myeloid cells and microglia are believed to mediate oligodendrocyte damage through generation and secretion of toxic and/or proinflammatory mediators [2]. Very recently, the role of macrophages has been extensively studied in the pathogenesis of MS. Indeed, macrophages have been shown to play a substantial role in the pathogenesis of T1D [17]. Alongside the macrophages that display the classical pro-inflammatory phenotype, designated “M1” macrophages, another macrophage sub-type, designated “M2”, is responsible for wound healing and tissue-remodeling functions. The degree to which a given macrophage bears M1 or M2 characteristics is termed “polarization” [18]. While the pro-inflammatory classical macrophages (M1) enhance the progression and severity of MS through cooperation with T cells, anti-inflammatory macrophages (M2) appeared to have beneficial effects on the outcome of the disease [19,20]. M1 macrophages are characterized by high levels of reactive oxygen species (ROS), nitric oxide (NO), CD11c, TNF-α and IL-1β, while M2 macrophages are characterized by high levels of arginase 1 (Arg-1), CD206 (Mac1), CD163, CD301, Fizz1 and Ym1 [21].

 

Source:

http://doi.org/10.18632/aging.101786

 

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