Astrocyte-produced HB-EGF limits autoimmune CNS pathology [RNA-Seq]

Central nervous system (CNS) resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including Multiple Sclerosis (MS). Several studies have demonstrated the involvement of pro- inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from MS patients in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a novel modulator of autoimmune CNS inflammation and potential therapeutic target in MS. Comparative gene expression profiling analysis of RNA-seq data for ACSA2 positive astrocytes during peak and late stage worsening of experimental autoimmune encephalomyelitis (EAE)

中枢神经系统（Central nervous system, CNS）驻留细胞，例如小胶质细胞（microglia）、少突胶质细胞（oligodendrocytes）与星形胶质细胞（astrocytes），因其在包括多发性硬化症（Multiple Sclerosis, MS）在内的中枢神经系统病理过程中的作用，正日益受到学界广泛关注。多项研究已证实，促炎性胶质细胞亚群参与了多发性硬化症及其动物模型中炎症事件的发病与传播进程。然而直至近期，人们才明确星形胶质细胞与小胶质细胞的固有异质性不仅可驱动炎症发生，还能通过直接与间接途径促进炎症消退。此类组织保护机制的失效可能会加重病情，并提升向多发性硬化症进展期转化的风险，而当前针对该阶段的可用治疗手段极为有限。本研究通过对多发性硬化症患者的脑脊液样本开展蛋白质组学分析，并结合实验研究，将肝素结合性表皮生长因子样生长因子（Heparin-binding EGF-like growth factor, HB-EGF）鉴定为中枢神经系统自身免疫性炎症中，介导急性炎症病变恢复所需的关键组织保护与抗炎效应分子。在中枢神经系统炎症早期，缺氧环境可驱动星形胶质细胞快速上调肝素结合性表皮生长因子样生长因子的表达，而促炎微环境则通过表观遗传修饰抑制具有营养支持功能的肝素结合性表皮生长因子样生长因子信号通路。此外，本研究在体外多种细胞类型中证实了肝素结合性表皮生长因子样生长因子的抗炎与组织保护作用，并在多发性硬化症的临床前小鼠模型中，于神经炎症的急性期与亚急性期通过鼻腔给药途径给予肝素结合性表皮生长因子样生长因子，成功缓解了疾病症状。综上，本研究鉴定出星形胶质细胞来源的肝素结合性表皮生长因子样生长因子及其表观遗传调控机制，可作为中枢神经系统自身免疫性炎症的新型调控因子，同时也是多发性硬化症潜在的治疗靶点。针对实验性自身免疫性脑脊髓炎（Experimental Autoimmune Encephalomyelitis, EAE）峰值期与晚期恶化阶段的ACSA2阳性星形胶质细胞的RNA测序数据，开展了比较基因表达谱分析。