The role of myeloid cell-specific ten eleven translocase 2 (TET2) in regulation of neuroinflammation

Abstract

Abstract Multiple Sclerosis (MS), is an inflammatory demyelinating disease of the central nervous system (CNS) believed to be autoimmune in etiology. Analysis of legions from MS patients, as well as studies in Experimental Autoimmune Encephalomyelitis (EAE), a murine model of MS, have indicated that myeloid cells play a critical role in the pathogenesis of CNS autoimmunity. Recently, Ten-Eleven Translocation 2 (TET2) was identified as a 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), a stable epigenetic mark. There is growing evidence that TET2 acts as a negative regulator of myeloid cell activation. Further, TET2 and 5hmC are reduced in peripheral blood mononuclear cells of MS patients compared with healthy volunteers. The objective of the current study is to investigate the hypothesis that reductions of TET2 expression and activity in myeloid cells is a critical step in the development of pro-inflammatory myeloid cells during CNS autoimmunity. Our laboratory has found that Tet2 transcripts levels and 5hmC content are reduced in CNS-infiltrating myeloid cells at the peak of EAE compared with the onset or late stages. Adoptive transfer of encephalitogenic CD4+ Th17 cells into Tet2−/+ mice lead to an exacerbated clinical course compared with their Tet2+/+ counterparts. Our data suggests that TET2 expression and activity is dysregulated in myeloid cells and limits neuroinflammation and chronic neurological disability. Interventions that promote Tet2 expression in myeloid cells may ameliorate EAE and, by extension, MS.