NF-kB/MyD88调控巨噬细胞亚型转化在MS/GBS发病机制中的作用及潜在临床应用

Multiple sclerosis (MS) and Guillain-Barré syndrome (GBS) are the most common inflammatory demyelinating diseases in the nervous system, which is an important cause of leading to disability in young adults. So far there is lack of significant efficacy of immunotherapy in the diseases. Macrophages and its subtypes (M1/M2) play a key role in the pathogenesis of MS/GBS and their animal models, experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). Based on our previous studies on macrophages, the present project intends to clarify that M1 cells play a inflammatory role in myelin damage and inflammatory response, and M2 with anti-inflammatory property by separating brain， spinal cord and lymphatic tissues from EAE/EAN mice and collect target organs and blood samples from MS/GBS patients using pathological, immunological and other related technologies. We will investigate the regulating role of the intracellular signal transduction molecules NF-κB and MyD88 in the shifting M1 to M2 via gene silencing, gene knockout and other related technologies; in vitro polarization of EAE/EAN macrophage to M2 subtype and reinfusion them to EAE/EAN mice. We further observe the M2 cell therapeutic effect on EAE/EAN, which provides a theoretical basis and the new methods for clinical treatment of MS/GBS.

多发性硬化(MS)及吉兰-巴雷综合征(GBS)是神经系统最常见的炎性脱髓鞘性疾病，也是导致青壮年残疾的重要原因，目前尚缺乏有效的特异性免疫治疗手段。巨噬细胞及其亚型 (M1/M2)在MS/GBS及其动物模型实验性自身免疫性脑脊髓炎(EAE)/实验性自身免疫性神经炎(EAN)的发病过程中起到关键作用。本课题拟在既往我们研究巨噬细胞作用的基础上，通过分离EAE/EAN小鼠脑脊髓、神经和淋巴组织，收集MS/GBS患者脑、神经及血液标本，采用病理学、免疫学等技术，阐明M1细胞在髓鞘损伤和炎症反应中的致炎作用，及M2的抗炎作用；通过基因沉默、基因敲除等技术，探讨细胞内信号转导分子NF-κB及MyD88在M1向M2转化中的调节作用；并于体外诱导EAE/EAN小鼠巨噬细胞极化为M2细胞，并回输至EAE/EAN小鼠体内，进一步观察其对EAE/EAN的治疗作用，为临床治疗MS/GBS提供理论依据和新的方法。

多发性硬化(MS)及吉兰-巴雷综合征(GBS)是神经系统最常见的炎性脱髓鞘性疾病，也是导致青壮年残疾的重要原因，目前尚缺乏有效的特异性免疫治疗手段。巨噬细胞及其亚型 (M1/M2)在MS/GBS及其动物模型实验性自身免疫性脑脊髓炎(EAE)/实验性自身免疫性神经炎(EAN)的发病过程中起到关键作用。本课题拟在既往我们研究巨噬细胞作用的基础上，通过分离EAE/EAN小鼠脑脊髓，神经和淋巴组织，收集MS/GBS患者脑、神经及血液标本，采用病理学、免疫学等相关技术，阐明M1细胞在髓鞘损伤和炎症反应中的致炎作用，及M2的抗炎作用；通过基因沉默、基因敲除等技术，探讨细胞内信号转导因子NF-κB及MyD88在M1向M2转化中的调节作用；并于体外诱导EAE/EAN小鼠巨噬细胞极化为M2细胞，回输至EAE/EAN小鼠体内，进一步观察其对EAE/EAN的治疗作用，为临床治疗MS/GBS提供理论依据和新的方法。