p38MAPK/SGK1作用于NKT细胞分化与功能参与调控多发性硬化免疫反应

Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS) that often leads to disability in young adults. Experimental autoimmune encephalomyelitis (EAE) in mice is an experimental model that is used frequently to study multiple sclerosis. p38MAPK/SGK1 may play important role in immune reactions in MS/EAE. We have found increased NKT cells in peripheral blood (PB) and cerebrospinal fluid of MS patients. We also observed reduced severity of EAE mice with p38MAPK inhibitor treatment, accompanied with lower NKT cell number and lower IL-17A and IL-23 in PB. The function of p38MAPK/SGK1 in regulating NKT cells in MS/EAE is still unkown. In the present study, we will evaluate the functional role of p38MAPK/SGK1 in NKT cell differentiaton and function, and its role in regulating MS/EAE progression, by using MS PB and NKT cell-deficient mice. This is the first time to clarify the functional role of p38MAPK/SGK1 in regulating immune recations in MS/EAE through modulating NKT cell function.

多发性硬化(MS)确切发病机制不明,诊治困难。p38MAPK信号通路在MS/EAE的致病中可能发挥重要作用，SGK1为该通路下游蛋白。NKT细胞为免疫调节细胞。前期研究中我们首先在MS患者外周血和脑脊液中均发现NKT细胞增多；其次在对EAE鼠应用p38MAPK抑制剂后发现神经功能评分改善，CNS组织SGK1蛋白表达明显降低，外周血NKT细胞数量减少及IL-17A和IL-23明显降低。目前直接针对p38MAPK/SGK1调控MS/EAE中NKT细胞分化与功能的研究尚未见报道。本研究将利用MS患者外周血、EAE小鼠及NKT细胞缺失小鼠等，在体外及体内水平对p38MAPK/SGK1如何调控NKT细胞分化与功能、与MS/EAE发生发展的关系及NKT细胞在其中的介导作用进行详细的研究，首次阐明p38MAPK/SGK1如何作用于NKT细胞调控MS免疫反应，为MS早期诊断和治疗提供新的线索和理论依据。

p38MAPK信号通路在MS/EAE的致病中可能发挥重要作用，SGK1为该通路下游蛋白，既往在神经免疫研究领域极少被涉及。自然杀伤T（NKT）细胞是一类特殊免疫调节T细胞亚群，参与介导包括自身免疫在内的多种免疫反应。本研究利用EAE小鼠以及NKT细胞缺失小鼠等动物模型，在体外及体内水平对p38MAPK/SGK1与EAE发生发展的关系及NKT细胞在其中的介导作用进行详细的研究，以明确三者之间的调控关系。通过以上研究内容的实施，我们证实NKT细胞在EAE免疫反应中主要发挥抑制性调控作用，p38MAPK/SGK1对NKT细胞功能具有直接调控作用，同时SGK1可能在参与EAE免疫反应的其它细胞中发挥促炎作用。本研究结果为后续相关研究奠定了理论基础，提供了方向和依据。