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

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dc.article.number292
dc.contributor.authorPrado, Carolina
dc.contributor.authorOsorio Barrios, Francisco
dc.contributor.authorFalcón, Paulina
dc.contributor.authorEspinoza, Alexandra
dc.contributor.authorSaez, Juan José
dc.contributor.authorYuseff Sepúlveda, María Isabel
dc.contributor.authorPacheco, Rodrigo
dc.date.accessioned2021-12-22T16:24:07Z
dc.date.available2021-12-22T16:24:07Z
dc.date.issued2021
dc.date.updated2021-12-19T01:03:12Z
dc.description.abstractAbstract 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.
dc.format.extent20 páginas
dc.fuente.origenAutoarchivo
dc.identifier.citationJournal of Neuroinflammation. 2021 Dec 17;18(1):292
dc.identifier.doi10.1186/s12974-021-02338-1
dc.identifier.urihttps://doi.org/10.1186/s12974-021-02338-1
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/63078
dc.information.autorucFacultad de Ciencias Biológicas ; Yuseff Sepúlveda, María Isabel ; 0000-0001-8172-3785 ; 12456311
dc.issue.numeroNo. 1
dc.language.isoen
dc.nota.accesoContenido completo
dc.revistaJournal of Neuroinflammationes_ES
dc.rightsacceso abierto
dc.subjectRegulatory B lymphocyteses_ES
dc.subjectAntigen-presenting cellses_ES
dc.subjectChemokine receptorses_ES
dc.subjectNeuroinfammationes_ES
dc.subjectExperimental autoimmune encephalomyelitises_ES
dc.subjectCentral nervous system hominges_ES
dc.subject.ddc570
dc.subject.deweyBiologíaes_ES
dc.subject.otherLinfocitos Bes_ES
dc.subject.otherCélulas con antígeno presente - Inmunologíaes_ES
dc.titleDopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity
dc.typeartículo
sipa.codpersvinculados12456311
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