Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Abstract

Background: Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T-cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS.Methods: Mice harbouring Drd3-deficient or Drd3-suficient B-cells were generated by bone marrow transplantation into recipient mice devoid of B-cells. In these mice we compare the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC function of B-cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B-cells display a fundamental APCs function in the CNS. Results: Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3- stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells.Conclusion: Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

GPR43 stimulation on TCRαβ+ intraepithelial colonic lymphocytes inhibits the recruitment of encephalitogenic T-cells into the central nervous system and attenuates the development of autoimmunity

“…These results suggest that TCRαβ + T-cells present in the colonic epithelium during the peak of EAE manifestation leave the gut mucosa to reach the CNS during the recovery stage of the disease (25 dpi). Since the chemokine receptor CXCR3 has been involved in lymphocyte in ltration into the CNS upon neuroin ammation [37][38][39][40][41][42], we determined the dynamics of the expression of this receptor on TCRαβ + T-cells obtained from the colonic epithelium and CNS during different stages of EAE development. Interestingly, we observed a signi cant increase of CXCR3 + TCRαβ + T-cells in the colonic epithelium at 15 dpi, followed by a substantial decrease at 25 dpi (Fig.…”

“…7A). Since CXCL11-mediated stimulation of CXCR3 has been consistently involved in the lymphocyte in ltration into the CNS in mice and humans upon CNSautoimmunity [37][38][39][40][41][42], we next addressed the question of whether propionate-mediated GPR43 stimulation was able to affect the CXCL11-CXCR3 migration of IEL TCRαβ + T-cells. For this purpose, we treated IEL with or without propionate for 1 h and then placed them on the top chamber to determine the extent of TCRαβ + T-cells migration towards CXCL11 into the bottom transwell chamber.…”