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

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 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.