The Role of Myeloid Cell-Specific Ten-Eleven Translocase 2 (TET2) in Regulation of Neuroinflammation

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PROJECT SUMMARY Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) believed to be autoimmune in etiology. Analysis of MS lesions, as well as studies in experimental autoimmune encephalomyelitis (EAE), a murine model of MS, have indicated that myeloid cells are likely a critical component of the pathogenesis of CNS autoimmunity. Recently, Ten-Eleven Translocase 2 (TET2) was identified as a genetic susceptibility locus for MS. TET2 is a Fe(III)-, α-ketoglutarate-dependent enzyme that catalyzes the oxidation of methylated cytosine to 5’-hydroxymethyl cytosine (5hmC) and promotes active demethylation. 5hmC is a stable epigenetic mark that can either activate or repress gene expression in a cell- and loci-dependent manner. There is growing evidence that TET2 acts as a negative regulator of myeloid cell activation and function, promoting a homeostatic or anti-inflammatory cell state. My hypothesis is that TET2 restrains the pro- inflammatory functions of myeloid cells to limit inflammation, neurological damage, and disability during CNS autoimmunity. Supporting this hypothesis, TET2 and 5hmC were found to be reduced in peripheral blood mononuclear cells of MS patients when compared with controls. Preliminary data from our laboratory demonstrates that the reduction of TET2 and 5hmC in peripheral blood mononuclear cells is recapitulated in EAE, and that TET2 transcripts and 5hmC content are further reduced in CNS-infiltrating myeloid cells compared with the periphery. Additionally, adoptive transfer of encephalitogenic Th17 cells into Tet2+/- mice led to an exacerbated clinical course compared with Tet2+/+ mice. To continue addressing my hypothesis, I will first examine the impact of TET2 deficiency in myeloid cells on clinical and pathological outcomes of EAE (Aim 1). I will do this by examining the EAE disease course, pathology, and cellular infiltration in mice where Tet2 is knocked out specifically in myeloid cells using a Cre/lox genetic system. Additionally, I will identify the targets of TET2 in CNS-infiltrating myeloid cells, such as the suppression of pro-inflammatory cytokine production and the conversion of myeloid cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype (Aim 2). Completion of these aims will contribute to the fields of neuroimmunology and epigenetics by exploring a novel mechanism of myeloid cell regulation during CNS autoimmunity, and may lead to the discovery of novel myeloid cell-specific therapeutic targets for the treatment of MS and related disorders.