Shen Zhi-Yuan, Zheng Yi, Pecsok Maggie K, Wang Ke, Li Wei, Gong Min-Jie, Wu Feng, Zhang Lin
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xi'an Jiaotong University, Xi'an, China.
School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Front Immunol. 2021 Mar 25;12:589200. doi: 10.3389/fimmu.2021.589200. eCollection 2021.
Experimental autoimmune encephalomyelitis (EAE) is a classical murine model for Multiple Sclerosis (MS), a human autoimmune disease characterized by Th1 and Th17 responses. Numerous studies have reported that C-reactive protein (CRP) mitigates EAE severity, but studies on the relevant pathologic mechanisms are insufficient. Our previous study found that CRP suppresses Th1 response directly by receptor binding on naïve T cells; however, we did not observe the effect on Th17 response at that time; thus it remains unclear whether CRP could regulate Th17 response. In this study, we verified the downregulation of Th17 response by a single-dose CRP injection in MOG-immunized EAE mice while the direct and indirect effects of CRP on Th17 response were differentiated by comparing its actions on isolated CD4 T cells and splenocytes , respectively. Moreover, the immune cell composition was examined in the blood and CNS (Central Nervous System), and a blood (monocytes) to CNS (dendritic cells) infiltration pathway is established in the course of EAE development. The infiltrated monocyte derived DCs (moDCs) were proved to be the only candidate antigen presenting cells to execute CRP's function. Conversely, the decrease of Th17 responses caused by CRP disappeared in the above and studies with FcR2B mice, indicating that FcR2B expressed on moDCs mediates CRP function. Furthermore, peripheral blood monocytes were isolated and induced to establish moDCs, which were used to demonstrate that the antigen presenting ability of moDCs was attenuated by CRP through FcR2B, and then NF-B and ERK signaling pathways were manifested to be involved in this regulation. Ultimately, we perfected and enriched the mechanism studies of CRP in EAE remission, so we are more convinced that CRP plays a key role in protecting against EAE development, which may be a potential therapeutic target for the treatment of MS in human.
实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症（MS）的经典小鼠模型，MS是一种以Th1和Th17反应为特征的人类自身免疫性疾病。大量研究报道，C反应蛋白（CRP）可减轻EAE的严重程度，但相关病理机制的研究尚不充分。我们之前的研究发现，CRP通过与未成熟T细胞上的受体结合直接抑制Th1反应；然而，当时我们未观察到其对Th17反应的影响；因此，CRP是否能调节Th17反应仍不清楚。在本研究中，我们通过在髓鞘少突胶质细胞糖蛋白（MOG）免疫的EAE小鼠中单次注射CRP来验证其对Th17反应的下调作用，同时通过比较CRP对分离的CD4 T细胞和脾细胞的作用，分别区分其对Th17反应的直接和间接影响。此外，我们检测了血液和中枢神经系统（CNS）中的免疫细胞组成，并在EAE发展过程中建立了一条从血液（单核细胞）到CNS（树突状细胞）的浸润途径。已证实浸润的单核细胞衍生树突状细胞（moDCs）是执行CRP功能的唯一候选抗原呈递细胞。相反，在上述研究中，用FcR2B小鼠进行实验时，CRP引起的Th17反应降低消失，这表明moDCs上表达的FcR2B介导了CRP的功能。此外，分离外周血单核细胞并诱导其形成moDCs，用于证明CRP通过FcR2B减弱了moDCs的抗原呈递能力，随后发现核因子-κB（NF-κB）和细胞外信号调节激酶（ERK）信号通路参与了这一调节过程。最终，我们完善并丰富了CRP在EAE缓解中的机制研究，因此我们更加确信CRP在预防EAE发展中起关键作用，这可能是治疗人类MS的一个潜在治疗靶点。
