Endogenous ERMAP Affects T‐Cell Function in EAE Mice

ABSTRACT Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease (AID) mediated by myelin‐reactive CD4 + T cells. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of human MS. Erythrocyte membrane‐associated protein (ERMAP) is a novel erythrocyte‐specific adhesion/receptor molecule associated with erythrocyte adhesion. We have previously characterised it as a novel inhibitory immune checkpoint molecule and demonstrated that recombinant ERMAP proteins ameliorate EAE; however, the specific mechanism of action of ERMAP and the effects of endogenous ERMAP on T‐cell function are largely unknown. In this study, we investigate the role of endogenous ERMAP in T‐cell and macrophage homeostasis and EAE development. We show here that erythrocyte membrane‐associated protein (ERMAP) gene knockout (ERMAP −/− ) mice have increased numbers of T cells and pro‐inflammatory M1 macrophages and enhanced T‐cell activation, as compared to wild‐type (ERMAP +/+ ) mice. When induced to develop EAE, ERMAP −/− mice have more severe EAE symptoms and pathology, which are related to increased numbers of T cells (especially Th1 and Th17 T cells) and M1 macrophages, enhanced activation of T cells, and increased generation of inflammatory cytokines, but decreased proportion of Th2 T cells, regulatory T cells (Tregs), and anti‐inflammatory M2 macrophages. Global gene analysis by RNA‐seq shows that signalling molecules in the peroxisome proliferator‐activated receptor (PPAR) pathway are decreased in ERMAP −/− mice. Our results suggest that endogenous ERMAP plays an important role in T‐cell and macrophage homeostasis and EAE development.