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

Background Recent 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. Methods Mice 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. Results Our data show that the selective Drd3 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. Conclusions Our 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..

Medienart:	E-Artikel

Erscheinungsjahr:	2021
Erschienen:	2021

Enthalten in:	Zur Gesamtaufnahme - volume:18
Enthalten in:	Journal of neuroinflammation - 18(2021), 1 vom: 17. Dez.

Sprache:	Englisch

Beteiligte Personen:	Prado, Carolina [VerfasserIn] Osorio-Barrios, Francisco [VerfasserIn] Falcón, Paulina [VerfasserIn] Espinoza, Alexandra [VerfasserIn] Saez, Juan José [VerfasserIn] Yuseff, María Isabel [VerfasserIn] Pacheco, Rodrigo [VerfasserIn]

Links:	Volltext [kostenfrei]

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

Anmerkungen:	© The Author(s) 2021

doi:	10.1186/s12974-021-02338-1

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	OLC2128818621