Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity
© 2021. The Author(s)..
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 |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
Journal of neuroinflammation - 18(2021), 1 vom: 17. Dez., Seite 292 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Prado, Carolina [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.03.2022 Date Revised 21.03.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12974-021-02338-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM334568919 |
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| 245 | 1 | 0 | |a Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity |
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| 500 | |a Date Completed 21.03.2022 | ||
| 500 | |a Date Revised 21.03.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antigen-presenting cells | |
| 650 | 4 | |a Central nervous system homing | |
| 650 | 4 | |a Chemokine receptors | |
| 650 | 4 | |a Experimental autoimmune encephalomyelitis | |
| 650 | 4 | |a Neuroinflammation | |
| 650 | 4 | |a Regulatory B lymphocytes | |
| 650 | 7 | |a Drd3 protein, mouse |2 NLM | |
| 650 | 7 | |a Receptors, Dopamine D3 |2 NLM | |
| 650 | 7 | |a Dopamine |2 NLM | |
| 650 | 7 | |a VTD58H1Z2X |2 NLM | |
| 700 | 1 | |a Osorio-Barrios, Francisco |e verfasserin |4 aut | |
| 700 | 1 | |a Falcón, Paulina |e verfasserin |4 aut | |
| 700 | 1 | |a Espinoza, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Saez, Juan José |e verfasserin |4 aut | |
| 700 | 1 | |a Yuseff, María Isabel |e verfasserin |4 aut | |
| 700 | 1 | |a Pacheco, Rodrigo |e verfasserin |4 aut | |
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