Tumor Necrosis Factor Receptor 2 Promotes Neuroprotection During Chronic Autoimmune Neuroinflammation
Tumor necrosis factor alpha (TNF) is a pleiotropic inflammatory cytokine that has been associated with pathogenesis of several autoimmune diseases, including multiple sclerosis (MS). Consequently, TNF-blocking drugs have been widely used to treat many inflammatory conditions and have proven highly effective. However, treatment of MS patients with anti-TNF drugs leads to disease exacerbation and severe demyelination. This effect has been specifically associated with lack of TNF signaling through its receptor, TNFR2. However, the underlying mechanisms are not fully understood. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model used to study MS. Our lab has generated HLA-DR2b+/+ TNFR2-/- mice to study the role of TNFR2 signaling in EAE in the context of HLA-DR2b (DRB1*1501), a haplotype strongly associated with MS. We found that these mice developed progressive EAE characterized by increased demyelinating lesions. Strikingly, passive immunization of EAE induction studies revealed that this phenotype was not due to exacerbated T cell responses, but rather was associated with suppression of oligodendrocyte progenitor cells (OPCs) requirement or function, and chronic astrogliosis in CNS demyelinating lesions during the chronic phase of EAE. Our studies provide key insights into CNS repair and regulatory mechanisms controlled by TNF via TNFR2 during inflammation. The latter may be an excellent target for the development of novel therapeutic strategies for treating MS.