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 (PDGFR?-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.
Multiple sclerosis (MS) is the most common neurological disease in young adults, affecting approximately 400,000 individuals in the United States and more than 2.5 million worldwide. Despite the general consensus on the autoimmune component of MS, its etiology remains unknown. For this reason, there is no cure for MS and current treatment regimens, often associated with severe side effects, are based on combinations of 'disease modifying' drugs that can help slow down disease progression, reduce relapses and improve quality of life. None of such treatments, however, can halt or revert the damage to myelin and axons associated with the chronic progressive form of the disease, and are cause of permanent disability. To address the pressing need for long term reparative therapies, new pharmacological targets must be identified. This can only happen when the mechanisms of the underlying neurodegenerative process are elucidated. On this basis, our primary objective in this application is to investigate the mechanisms whereby TNFR2 expressed in oligodendrocyte precursor cells and mature oligodendrocytes induces its protective functions in the EAE model of MS. Our studies will be highly relevant in advancing the general knowledge on the role of TNFR2 signaling in neuro-immune disease and in the development of a possible new therapeutic intervention for progressive MS, in line with the current priorities of the MS research community.
