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.Conclusions. 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-signalling in B-cells as a key regulator of CNS-autoimmunity..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
ResearchSquare.com - (2022) vom: 29. Juli Zur Gesamtaufnahme - year:2022 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Prado, Carolina [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.21203/rs.3.rs-41605/v3 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XRA034762477 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XRA034762477 | ||
| 003 | DE-627 | ||
| 005 | 20230429193637.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 220113s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.21203/rs.3.rs-41605/v3 |2 doi | |
| 035 | |a (DE-627)XRA034762477 | ||
| 035 | |a (ResearchSquare)10.21203/rs.3.rs-41605/v3 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Prado, Carolina |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dopaminergic Stimulation Leads B-cell Infiltration into the Central Nervous System upon Autoimmunity |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a 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.Conclusions. 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-signalling in B-cells as a key regulator of CNS-autoimmunity. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Osorio-Barrios, Francisco |e verfasserin |4 aut | |
| 700 | 1 | |a Espinoza, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Saez, Juan J |e verfasserin |4 aut | |
| 700 | 1 | |a Yuseff, María I |e verfasserin |4 aut | |
| 700 | 1 | |a Pacheco, Rodrigo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ResearchSquare.com |g (2022) vom: 29. Juli |
| 773 | 1 | 8 | |g year:2022 |g day:29 |g month:07 |
| 856 | 4 | 0 | |u https://doi.org/10.1186/s12974-021-02338-1 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.21203/rs.3.rs-41605/v3 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XRA | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2022 |b 29 |c 07 | ||