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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.
Highlights
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]
To confirm the M2 macrophage polarization by IL-4, we examined the mRNA levels of Arginase 1 (Arg-1), Ym-1 and Fizz-1, three M2 macrophage markers
We found that IL-4 induced about 40 times’ increase in Arg-1 mRNA (Figure 1A), about 400 times’ increase in Ym-1 mRNA (Figure 1B), and about 10 times’ increase in Fizz-1 mRNA (Figure 1C)
Summary
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]. In the initial phase of MS, peripheral macrophages are recruited to the CNS, where they participate in the initiation, progression and development of disease, through their interaction with other inflammatory cells and residential microglia [3]. Microglia/macrophages are predominantly activated to differentiate into classically activated macrophages www.aging-us.com ( called M1 macrophages) that release proinflammatory cytokines to enhance their damage to CNS tissue [4]. Microglia/macrophages in the inflamed CNS are extensively polarized to alternatively activated macrophage phenotype ( called M2 macrophages) that release anti-inflammatory and trophic cytokines to favor inflammation repression and tissue recovery [4]. While M1 macrophage polarization is induced by proinflammatory cytokine interferon-gamma (IFN-γ), M2 macrophage polarization is primarily induced by interleukin (IL)-4 and IL-13 [5]
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