Systemic sclerosis
that upregulated secretion of chemerin by adventitial pulmonary fibroblasts and/or peripheral tissues may contribute to the patho- genesis of SSc-PAH. Interestingly, previous studies have suggested a role of chem- erin in both SSc and PAH pathogenesis. 26 27 45 In SSc patients, chemerin expression is increased in dermal endothelial cells; and circulating levels of chemerin correlated with occurrence of digital ulcers. 27 Chemerin expression was also decreased in dermal fibroblasts, due to autocrine TGF- β secretion and Fli1 deficiency; and serum chemerin levels correlated with mRSS. 27 Of note, CMKLR1 expression in SSc patients’ skin was similar to healthy controls’. 27 In PA from healthy rats, chemerin and CMKLR1 expression is detected in both endothelial cells and SMCs. 46 Exposure to chemerin potentiated vascular responses to vasoconstrictors (phenylephrine, endothelin-1 and serotonin) in rat PA and impaired acetylcholine-induced PA vasodilatation, by mechanisms involving at least partly NO signalling and oxidative stress. 46 In primary cultured PASMCs from healthy rats, expo- sure to chemerin induced a dose-dependent proliferation and migration (potentiated by combination with endothelin-1), 26 31 and reduced staurosporine-induced apoptosis. 26 Chemerin treat- ment did not alter gene expression of IL-6, IL-6R and IL-1 β , but increased TNF- α at high doses. 26 Healthy rat PASMCs exposed to chemerin up-regulated the ERK1/2 pathways; and treatment by an ERK inhibitor annulled the chemerin-induced prolifera- tion. 31 In the monocrotaline (MCT) rat model of PAH, chemerin- induced contraction of intrapulmonary arteries is increased compared with controls. 45 Lungs from MCT rats showed increased expression of CMKLR1 and production of various chemerin isoforms (possibly due to glycosylation) compared with healthy animals. 45 Expression of CMKLR1 in MCT rats was increased in SMCs but decreased expression in endothelial cells compared with controls. 31 45 Finally, in studies performed in other vascular diseases, chemerin was able to induce angio- genesis in vitro 47 ; and knockdown of chemerin significantly inhibited SMC proliferation and neointimal hyperplasia in a rat model of vascular injury induced by balloon angioplasty. 48 Overall, these data suggest that the chemerin-CMKLR1 axis could contribute to the pathogenesis of SSc-PAH through vascular effects but could also be involved in the fibrotic and inflammatory events occurring during the disease. Strengths and limitations Our study draws strength from the sample collection on the same day as RHC (which allowed to perform accurate haemodynamic correlations), its wide-scale proteomic approach, the validation of our results on an independent cohort, and evidences for the pathophysiological relevance of the candidate biomarkers. It also has limitations. First, we limited our study popula- tion to untreated patients with lcSSc and non-extensive ILD, so that our biomarker screening would not be interfered with by an active cutaneous or interstitial lung involvement, nor by the effect of PAH-specific therapy. Although it allowed us to generate reproducible results in this specific subgroup, it also limited the generalisability of our findings. Further studies should try to investigate the relevance of chemerin as a PVR surrogate in other causes of PH (especially groups 2 and 3), as well as its PAH-specificity in other patient subgroups (notably dcSSc and extensive ILD). Second, although we screened a large number of candidate biomarkers, more recent panels now include several thousand proteins, that were not tested here. Third, as we wanted to obtain reliable hits, we used statistical methods that limited the risk of false discoveries. Due to this stringent
compared with non-SSc controls; and its protein was not detected by immunostaining. This discrepancy may reflect difficulties in detecting this secreted protein, limitations of the staining anti- body or lack of mRNA translation, possibly suggesting extrapul- monary production. In our previous work detailing scRNAseq data in iPAH patients, chemerin was also expressed primarily by fibroblasts and upregulated 2.075-fold. 44 These data suggest Figure 5 Representative images of lung sections immunostained with DAPI (blue), α -SMA (green) and CMKLR1 (red) from non-SSc controls (top row), SSc-no PAH (middle row) and SSc-PAH (bottom row). Scale bar=50 µm in all sections. α -SMA, a-smooth muscle actin; DAPI, 4',6-diamidino-2-phénylindole; PAH, pulmonary arterial hypertension; SSc, systemic sclerosis.
Figure 6 Proliferation of PA-SMCs from idiopathic PAH patients, after stimulation with serum from SSc-PAH and SSc-no PAH patients, in the presence or absence of α -NETA. α -NETA: 2-(anaphthoyl) ethyltrimethylammonium iodide; BrdU, 5-bromo-2-deoxyuridine; i, idiopathic; PAH, pulmonary arterial hypertension; PA-SMC, pulmonary arterial smooth muscle cells; SSc, systemic sclerosis.
Sanges S, et al . Ann Rheum Dis 2023; 82 :365–373. doi:10.1136/ard-2022-223237
371
Powered by FlippingBook