Artikel
Monocytic angiotensin and endothelin receptor expression and their clinical relevance in systemic sclerosis
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Autoren
Veröffentlicht: | 12. September 2014 |
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Gliederung
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Background: Monocytes of SSc patients present an altered, profibrotic phenotype and highest expression of angiotensin(II) (ATR) and endothelin receptors (ETR) compared to other PBMC subtypes. Stimulating autoantibodies (aab) against AT1R and ETAR are elevated in SSc and associated with disease manifestations and mortality. SSc-IgG positive for these aabs has been shown to induce the production of the profibrotic chemokine CCL18 in PBMCs through the respective receptors.
The objective of this study was to identify whether expression of AT1R and ETAR and their functional counterparts AT2R and ETBR on circulating monocytes is altered in SSc and influenced by organ manifestations. In addition the functional relevance of the receptor expression was analyzed by measuring aab-mediated CCL18 production in PBMC with known receptor expression.
Methods: Protein receptor expression of AT1R, AT2R, ETAR and ETBR was measured on CD14+ monocytes of 29 SSc patients and 18 healthy donors by flow cytometry. PBMCs of additional 11 healthy donors were analyzed for receptor expression as well and in vitro stimulated with affinity purified IgG of SSc patients and normal controls. Afterwards, CCL18 concentration was measured in the supernatants by ELISA.
Results: CD14+ circulating monocytes of SSc patients present higher expression of AT1R, AT2R, ETAR and ETBR as well as an increased AT1R/AT2R ratio compared to healthy donors. ETAR/ETBR ratio was significantly reduced in SSc patients with lung fibrosis and correlated negatively with the modified Rodnan Skin Score (Spearman rank correlation’s coefficient r=-0.49, p<0.01).
PBMCs of healthy donors showed a significant higher concentration of CCL18 in supernatants when stimulated with SSc-IgG than with NC-IgG (p<0.0001). CCL18 induction by NC-IgG and SSc-IgG correlated significantly positively with the AT1R/AT2R ratio of monocytes (NC-IgG r=0.98, p<0.0001; SSc-IgG r=0.72, p=0.03) and negatively with the ETAR/ETBR ratio (NC-IgG r=-0.93, p=0.007; SSc-IgG r=-0.82; p=0.03).
Conclusion: High AT1R/AT2R but low ETAR/ETBR ratios on monocytes correspond to higher secretion of CCL18 suggesting a link between receptor expression and monocytic function. Since patients with lung fibrosis and high mRSS showed a reduced ETAR/ETBR ratio, imbalance of ATR and ETR may influence effects of aab in SSc and could serve as a marker for disease complications.