Article
B cells synthesize, sense and transport catecholamines to autonomously modulate regulatory B cell function
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Authors
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Nadine Honke
- Poliklinik und Funktionsbereich für Rheumatologie, Universitätsklinikum Düsseldorf, Abteilung für Rheumatologie, Hiller Forschungszentrum, Düsseldorf
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Birgit Opgenoorth
- Poliklinik und Funktionsbereich für Rheumatologie, Universitätsklinikum Düsseldorf, Abteilung für Rheumatologie, Hiller Forschungszentrum, Düsseldorf
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Matthias Schneider
- Poliklinik und Funktionsbereich für Rheumatologie, Universitätsklinikum Düsseldorf, Abteilung für Rheumatologie, Hiller Forschungszentrum, Düsseldorf
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Georg Pongratz
- Poliklinik und Funktionsbereich für Rheumatologie, Universitätsklinikum Düsseldorf, Abteilung für Rheumatologie, Hiller Forschungszentrum, Düsseldorf
| Published: | September 14, 2021 |
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Outline
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Introduction: Catecholamines provided by the sympathetic nervous system (SNS) promote anti-inflammatory regulatory B cells (Bregs), thus strongly influence the development and severity of inflammatory diseases like the rheumatoid arthritis (RA). However, during chronic inflammation the source of catecholamines is depleted due to loss of sympathetic nerve fibres at sites of inflammation. In the current study, we investigated if B cells are able to compensate for part of this local loss of catecholamines by producing and releasing their own catecholamines to autonomously modulate their Breg function.
Methods: On non-activated and anti-IgM/CpG-activated murine B cells, catecholamine production and their targeted influence in Breg development were investigated. The production of catecholamines and their transporters were monitored in splenic B cells by ELISA or flow cytometry. The catecholamine profile was analyzed in B cells and in the supernatant of B cell cultures. The direct effect of catecholamine-induced IL-10 expression was quantified in the supernatant of B cell cultures by ELISA or on mRNA-level by quantitative real-time PCR (qRT-PCR).
Results: Detection of catecholamines by competitive ELISAs demonstrated that dopamine and epinephrine are primarily detectable intracellularly in B cells, while most of norepinephrine was measurable in the supernatant 4h after activation (supernatant vs. B cells, n=4, dopamine: p*=0.0183; norepinephrine: p***=0.0005; epinephrine: p****=<0.0001). After long-term activation (24h), nearly all catecholamines were released from B cells (supernatant vs. B cells, n=4, dopamine: n.s.>0.05; norepinephrine and epinephrine: p****=<0.0001).
Furthermore, in unstimulated B cells, norepinephrine transporter (NET) was detected on the plasma membrane, whereas the vesicular monoamine transporter-1/ and -2 (VMAT-1 and VMAT2) were located intracellularly in B cells (surface vs. intracellular, n=7, NET: p***=0.0006; VMAT-1: p**=0.0043; VMAT-2: p*=0.0341).
Stimulation of ß-adrenergic receptor (ß-ADR) signaling enhanced CpG-induced IL-10 secretion (CpG vs. CpG+norepinephrine, n=6, p***=0.0010) and is able to increase IL-10 levels independently from CpG activation (Ctl vs. norepinephrine, n=6, p***0.0008).
Conclusion: In conclusion, our data show that B cells possess an endogenous catecholamine metabolism which is tightly involved in B cell activation and modulation of regulatory B cell function, therefore providing possible future therapeutic targets in RA.
Disclosures: None declared
