Systemic sclerosis
Figure 2 Differential expression of chemerin and correlation with PVR in the discovery and the validation cohorts. PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; RFU, relative fluorescence units; SSc, systemic sclerosis.
increased CMKLR1 mRNA production in PA-SMCs from iPAH vs control (online supplemental figure S2). Then, PA-SMCs from iPAH patients were stimulated with serum obtained from five SSc-PAH and five SSc-no PAH patients in the presence or absence of α -NETA (figure 6). Serum from SSc-PAH cases seemed to induce higher PA-SMC proliferation than serum from SSc-no PAH controls. This difference seemed neutralised in the presence of α -NETA. Overall, these findings suggest that serum from SSc-PAH patients seems to induce proliferation of PA-SMCs and that inhibition of CMKLR1 activation could partly abolish this phenomenon. DISCUSSION To our knowledge, this is the first study that focused on identi- fying a surrogate marker for haemodynamic severity in SSc-PAH using a wide-scale approach. Our results can be summarised as follows: (1) chemerin seems to be a potential surrogate marker for haemodynamic severity in SSc-PAH, as it showed robust correla- tions with PVR; (2) in lungs, chemerin mRNA was detected in fibroblasts, PA-SMCs/pericytes and mesothelial cell populations; (3) elevated chemerin serum levels and increased expression of its receptor CMKLR1 by PA-SMCs could contribute to SSc-PAH pathogenesis by inducing PA-SMC proliferation. Since PAH is characterised by progressive pulmonary vascular remodelling leading to increased PVR, PVR is thought to reflect the severity of this process. 13 As such, it can be used to monitor treatment efficacy and failure. Developing non-invasive methods to assess PVR is thus a major unmet need in the field of SSc- PAH management, that has only been scarcely investigated so far. 6 11 Although there is some dispersion on the scatterplots that could limit future works, the correlation between PVR and Chemerin as a surrogate marker for haemodynamic severity in SSc-PAH
both patients with SSc and SSc-PAH groups relative to non-SSc controls (figure 5). No difference was observed in chemerin staining between groups (online supplemental figure S1). Taken altogether, these data could suggest an upregulation in the expression pattern of the chemerin/CMRLK1 axis in SSc- PAH pulmonary vessels. The SSc-PAH serum-induced PA-SMC proliferation seems inhibited by a chemerin-CMKLR1 inhibitor To further examine the functional consequences of these changes on PA-SMC proliferation, we next determined the efficacy of the CMKLR1 antagonist α -NETA to attenuate the proliferation of PA-SMCs derived from iPAH patients. First, we confirmed an
Figure 3 Differential expression of chemerin in different SSc patient groups. DC, diffuse cutaneous; ext ILD, extensive interstitial lung disease; HC, healthy controls; lc, limited cutaneous; PAH, pulmonary arterial hypertension; RFU, relative fluorescence units; SSc, systemic sclerosis.
Sanges S, et al . Ann Rheum Dis 2023; 82 :365–373. doi:10.1136/ard-2022-223237
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