RGC-32 enhances experimental autoimmune encephalomyelitis by promoting Il-17 and GM-CSF production

Abstract

Abstract Response Gene to Complement (RGC)-32 is an intracytoplasmatic protein expressed in a variety of cells in response to sublytic complement activation, TGF-β and several growth factors. Upon activation it translocates into the nucleus and plays an important role in cell proliferation, migration, angiogenesis and TGF-β induced epithelial mesenchymal transition and fibrosis. We have recently reported that RGC-32 promotes Th17 but not Treg, Th1 or Th2 differentiation in murine CD4 T cells in vitro. To evaluate the relevance of RGC-32 in an IL-17 dependent inflammatory condition we induced EAE in WT and RGC-32−/− mice by immunization with MOG35–55 peptide emulsified in CFA. The timing of disease onset was similar in both groups of mice. However, at peak disease, RGC-32−/− mice had significantly lower clinical scores. The attenuated EAE phenotype was confirmed by histopathologic examination of the spinal cords that showed fewer inflammatory infiltrates and demyelination foci in RGC-32−/− than in WT EAE mice. The percentage and absolute number of IL-17+ and GM-CSF+CD4+ T cells were significantly lower in the CNS of RGC-32−/− EAE mice. The percentage and number of IFNγ+ and FoxP3+ CD4+ T cells did not differ between WT and RGC-32−/− EAE mice. RGC-32 deficiency did not alter antigen specific expansion of RGC-32−/− spleen cells in response to MOG35-55 peptide. Transfer of WT CD4+ T cells into WT or RGC-32−/− mice before MOG immunization resulted in EAE of similar severity suggesting that the attenuated EAE phenotype in RGC-32−/− mice is T-cell-mediated. These data suggest that RGC-32 exerts a proinflammatory role in EAE by promoting Th17 immune responses and the generation of GM-CSF and that RGC-32 blockade might be a novel therapeutic strategy in MS.