Molecular mechanisms of the protective function of oligodendroglial TNFR2: a new therapeutic target in neuro-immune disease

 描述（由申请人提供）：肿瘤坏死因子（TNF）是一种多效性细胞因子，参与调节许多生理和病理过程，如炎症、癌症、自身免疫和感染。TNF还与各种神经系统疾病的发展有关，包括多发性硬化症（MS）。TNF以两种生物活性形式存在，即跨膜（tmTNF）和可溶性（solTNF），其功能由TNF受体1（TNFR 1）和TNF受体2（TNFR 2）介导。由于它们不同的结合亲和力，solTNF仅通过TNFR 1发出信号，而tmTNF通过TNFR 1和TNFR 2发出信号。由这两种受体激活的细胞过程通常是相反的：TNFR 1介导细胞凋亡和慢性炎症，TNFR 2介导细胞存活、炎症消退、免疫和髓鞘形成。许多研究已经强调了区分solTNF和tmTNF的功能的重要性，并且已经将MS及其动物模型实验性自身免疫性脑脊髓炎（EAE）与solTNF通过TNFR 1的有害作用相关联。在我们自己对MS的MOG 35 -55 EAE模型的研究中，我们不仅证明了solTNF是有害的，而且证明了tmTNF是保护性的，并且对于修复和髓鞘再生是重要的（Brambilla et al.，Brain 2011）。我们发现，用选择性solTNF阻断剂XPro 1595治疗的小鼠从EAE诱导的瘫痪中恢复。这与神经保护、改善髓鞘完整性和增加髓鞘再生有关，表明tmTNF可以通过直接作用于少突胶质细胞谱系的细胞来发挥其保护作用。这在我们实验室产生的少突胶质细胞特异性TNFR 2条件性KO小鼠（CNP-cre：TNFR 2fl/fl小鼠）中的初步研究中得到证实，其中我们证明从该细胞群中消融TNFR 2导致EAE病理学恶化、炎症增加、轴突损伤增加和髓鞘再生减少。我们的假设是少突胶质细胞中的TNFR 2调节下游信号级联，调节两个不同但同样重要的功能恢复过程：1）少突胶质细胞存活、增殖、分化、髓鞘形成/髓鞘再生的内在能力; 2）炎症反应。我们将通过我们实验室中生成的新动物模型来解决这一假设，其中TNFR 2仅从少突胶质细胞前体细胞（PDGFRα-creER：Rosa 26-EYFP：TNFR 2fl/fl小鼠）或髓鞘形成少突胶质细胞（PLP-creER：Rosa 26-EYFP：TNFR 2fl/fl小鼠）中消除。本申请的目的是更好地理解少突胶质细胞TNFR 2在神经免疫疾病中保护功能的分子机制。我们相信，阐明这些机制是能够通过开发在疾病过程中增强TNFR 2信号传导的策略来利用TNFR 2活化在神经免疫疾病中的治疗潜力的关键。

 DESCRIPTION (provided by applicant): Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in the regulation of numerous physiological and pathological processes such as inflammation, cancer, autoimmunity and infection. TNF is also linked to the development of various neurological disorders, including multiple sclerosis (MS). TNF exists in two biologically active forms, transmembrane (tmTNF) and soluble (solTNF), whose functions are mediated by TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Due to their different binding affinities, solTNF signals only via TNFR1, while tmTNF signals through both TNFR1 and TNFR2. The cellular processes activated by the two receptors are often opposite: TNFR1 mediates apoptosis and chronic inflammation, TNFR2 mediates cell survival, resolution of inflammation, immunity and myelination. Numerous studies have underscored the importance of distinguishing between the functions of solTNF and tmTNF, and have associated MS and its animal model experimental autoimmune encephalomyelitis (EAE) to the detrimental effects of solTNF via TNFR1. In our own work with the MOG35-55 EAE model of MS we demonstrated not only that solTNF is detrimental, but that tmTNF is protective and important for repair and remyelination (Brambilla et al., Brain 2011). We showed that mice treated with a selective solTNF blocker, XPro1595, recover from EAE-induced paralysis. This was associated with neuroprotection, improved myelin integrity and increased remyelination, suggesting that tmTNF could be exerting its protective effects by acting directly on cells of the oligodendrocyte lineage. This was confirmed in our preliminary studies in oligodendrocyte- specific TNFR2 conditional KO mice (CNP-cre:TNFR2fl/fl mice) generated in our lab, where we demonstrated that ablation of TNFR2 from this cell population resulted in worsening of the EAE pathology, increased inflammation, increased axonal damage and reduced remyelination. Our HYPOTHESIS is that TNFR2 in oligodendrocytes regulates downstream signaling cascades modulating two distinct but equally important processes for functional recovery: 1) the intrinsic capacity of oligodendrocytes to survive, proliferate, differentiate, myelinate/remyelinate; 2) the inflammatory response. We will address this hypothesis with new animal models generated in our lab where TNFR2 is ablated exclusively from oligodendrocyte precursor cells (PDGFRα-creER:Rosa26-EYFP:TNFR2fl/fl mice) or myelinating oligodendrocytes (PLP-creER:Rosa26-EYFP:TNFR2fl/fl mice). The OBJECTIVE of the present application is to gain a better understanding of the molecular mechanisms underlying the protective function of oligodendroglial TNFR2 in neuro-immune disease. We believe that elucidating these mechanisms is key to be able to harness the therapeutic potential of TNFR2 activation in neuro- immune disease by developing strategies to enhance TNFR2 signaling ad hoc during the course of the disease.