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

Journal of Neuroinflammation

Alexandra Espinoza¹  Paulina Falcón¹  Francisco Osorio-Barrios¹  Rodrigo Pacheco²  Carolina Prado²  Juan José Saez³  María Isabel Yuseff³ 

[1] Laboratorio de Neuroinmunología, Centro Ciencia & Vida, Fundación Ciencia & Vida, Avenida Zañartu #1482, Ñuñoa, 7780272, Santiago, Chile;Laboratorio de Neuroinmunología, Centro Ciencia & Vida, Fundación Ciencia & Vida, Avenida Zañartu #1482, Ñuñoa, 7780272, Santiago, Chile;Facultad de Medicina y Ciencia, Universidad San Sebastián, Providencia, 7510156, Santiago, Chile;Laboratory of Immune Cell Biology, Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, 8330025, Santiago, Chile;

关键词: Regulatory B lymphocytes;    Antigen-presenting cells;    Chemokine receptors;    Neuroinflammation;    Experimental autoimmune encephalomyelitis;    Central nervous system homing;   

DOI  :  10.1186/s12974-021-02338-1

来源: Springer

【 摘 要 】

BackgroundRecent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of 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 displays the highest affinity for dopamine, in B cells in animal models of MS.MethodsMice harbouring Drd3-deficient or Drd3-sufficient B cells were generated by bone marrow transplantation into recipient mice devoid of B cells. In these mice, we compared 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 APC-function in the CNS. APC-function was assessed in vitro by pulsing B cells with huMOG-coated beads and then co-culturing with MOG-specific T cells.ResultsOur data show that the selectiveDrd3 deficiency in B cells abolishes the disease development in the huMOG-induced EAE model. Mechanistic analysis indicates that although DRD3-signalling did not affect the APC-function of B cells, DRD3 favours the CNS-tropism in a subset of pro-inflammatory B cells in the huMOG-induced EAE model, an effect that was associated with higher CXCR3 expression. Conversely, the results show that the selective Drd3 deficiency in B cells exacerbates the disease severity in the pMOG-induced EAE model. Further analysis shows that DRD3-stimulation increased the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in the pMOG-induced EAE model.ConclusionsOur findings demonstrate that DRD3 in B cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B cells with APC-function and promoting CNS-homing of B cells with anti-inflammatory features. Thus, these results show DRD3-signalling in B cells as a critical regulator of CNS-autoimmunity.

【 授权许可】

CC BY