Emamnejad Rahimeh, Dass Mary, Mahlis Michael, Bozkurt Salome, Ye Sining, Pagnin Maurice, Theotokis Paschalis, Grigoriadis Nikolaos, Petratos Steven
Department of Neuroscience, Central Clinical School, Monash University, Prahran, VIC, Australia.
B', Department of Neurology, Laboratory of Experimental Neurology and Neuroimmunology, AHEPA University Hospital, Thessaloniki, Greece.
Front Pharmacol. 2022 Sep 5;13:934971. doi: 10.3389/fphar.2022.934971. eCollection 2022.
Multiple sclerosis (MS) is a heterogeneous autoimmune disease whereby the pathological sequelae evolve from oligodendrocytes (OLs) within the central nervous system and are targeted by the immune system, which causes widespread white matter pathology and results in neuronal dysfunction and neurological impairment. The progression of this disease is facilitated by a failure in remyelination following chronic demyelination. One mediator of remyelination is thyroid hormone (TH), whose reliance on monocarboxylate transporter 8 (MCT8) was recently defined. MCT8 facilitates the entry of THs into oligodendrocyte progenitor cell (OPC) and pre-myelinating oligodendrocytes (pre-OLs). Patients with MS may exhibit downregulated MCT8 near inflammatory lesions, which emphasizes an inhibition of TH signaling and subsequent downstream targeted pathways such as phosphoinositide 3-kinase (PI3K)-Akt. However, the role of the closely related mammalian target of rapamycin (mTOR) in pre-OLs during neuroinflammation may also be central to the remyelination process and is governed by various growth promoting signals. Recent research indicates that this may be reliant on TH-dependent signaling through β1-integrins. This review identifies genomic and non-genomic signaling that is regulated through mTOR in TH-responsive pre-OLs and mature OLs in mouse models of MS. This review critiques data that implicates non-genomic Akt and mTOR signaling in response to TH-dependent integrin receptor activation in pre-OLs. We have also examined whether this can drive remyelination in the context of neuroinflammation and associated sequelae. Importantly, we outline how novel therapeutic small molecules are being designed to target integrin receptors on oligodendroglial lineage cells and whether these are viable therapeutic options for future use in clinical trials for MS.
多发性硬化症（MS）是一种异质性自身免疫性疾病，其病理后遗症源于中枢神经系统内的少突胶质细胞（OLs），并成为免疫系统的攻击目标，这会导致广泛的白质病变，进而引起神经元功能障碍和神经损伤。慢性脱髓鞘后髓鞘再生失败会促使该疾病进展。甲状腺激素（TH）是髓鞘再生的一种介质，其对单羧酸转运蛋白8（MCT8）的依赖性最近已被明确。MCT8有助于TH进入少突胶质前体细胞（OPC）和前髓鞘形成少突胶质细胞（pre-OLs）。MS患者在炎症病灶附近可能表现出MCT8下调，这突出了TH信号传导以及后续下游靶向通路（如磷酸肌醇3激酶（PI3K）-Akt）受到抑制。然而，在神经炎症期间，雷帕霉素的密切相关哺乳动物靶点（mTOR）在pre-OLs中的作用可能也是髓鞘再生过程的核心，并且受各种生长促进信号调控。最近的研究表明，这可能依赖于通过β1整合素的TH依赖性信号传导。本综述确定了在MS小鼠模型中，通过mTOR在TH反应性pre-OLs和成熟OLs中调节的基因组和非基因组信号传导。本综述对涉及非基因组Akt和mTOR信号传导以响应pre-OLs中TH依赖性整合素受体激活的数据进行了批判。我们还研究了这是否能在神经炎症及相关后遗症的背景下驱动髓鞘再生。重要的是，我们概述了新型治疗性小分子如何被设计用于靶向少突胶质细胞谱系细胞上的整合素受体，以及这些是否是未来用于MS临床试验的可行治疗选择。
