Systemic sclerosis
Figure 4 Expression of CMKLR1, chemerin and α -smooth muscle actin mRNA in cell populations from SSc-PAH lungs assessed by single-cell RNA- sequencing. Top panels provide information from all cell populations; Bottom panels provide information on mesenchymal cell populations. α -SMA, α -smooth muscle actin; CMKLR1, chemokine-Like Receptor 1; PAH, pulmonary arterial hypertension; SSc, systemic sclerosis.
patient subgroups and compared chemerin levels between them, rather than including a broad heterogeneous patient population and assessed correlations. We believe that this allowed us to better ascertain the disease parameter responsible for elevated chemerin levels. Moreover, it is possible that the associations observed in dcSSc patients were in fact mediated by undiag- nosed PAH (as chemerin levels were reported to correlate with sPAP among dcSSc patients 29 ). Finally, this may also be explained by measurement of different chemerin isoforms. 30 In any case, further studies including well-defined homogeneous patient groups are needed to determine whether abnormal serum levels of chemerin are specific to PAH in SSc. Of note, serum chemerin levels were also studied in in patients with iPAH and were significantly increased compared with controls, with a satisfactory sensitivity (85.7%) and specificity (100%) at a concentration of 471.76 pg/mL. 31 Chemerin as a contributor to the pathogenesis of SSc-PAH Chemerin is pleiotropic protein that exerts multiple effects (acting to varying degrees as a chemokine, an adipokine and/or a growth factor) on different tissues (notably the immune system, the adipose tissue and the vasculature). 30 32 In blood vessels, chemerin can act on endothelial cells (regulating angiogenesis, cell adhesion and nitric oxide production) 33–36 as well as SMCs (inducing contraction, migration and proliferation). 37–40 As such, it has been implicated in several cardiovascular diseases, such as arterial hypertension, atherosclerosis, diabetic microangiopathy and pre-eclampsia. 30 32 Chemerin also yields proinflammatory effects by attracting and stimulating cytokine production from macrophages, dendritic cells and natural killer cells 41–43 ; and thus has also been involved in various immunologic conditions, such as rheumatoid arthritis and psoriasis. 30 In our work, chemerin mRNA was expressed primarily by fibroblasts and smooth muscle/pericytes, though not increased
chemerin serum levels was reproducible and can be described as moderate to strong based on Spearman coefficient values. In a recent work, 11 Bauer et al measured 313 proteins on sera from the DETECT cohort and identified a panel of 8 analytes capable of accurately discriminating SSc-PAH from SSc-no PAH patients. When testing the ability of these biomarkers to predict PVR, they found moderate correlations for a model comprised of 5 proteins: RAGE, NT-pro-BNP, IGFBP-7, SP-D and VCAM-1. Since this study focused primarily on identifying diagnostic biomarkers, and not PVR surrogates, further comparison with our results is challenging. Interestingly, the increase in chemerin concentrations appeared restricted to SSc-PAH patients in our study. Previous publications have reported on chemerin serum levels in SSc, although with conflicting results. 27–29 Akamata et al found similar values between SSc patients and healthy controls, and no difference between cutaneous subsets of the disease. 27 Chemerin levels correlated with modified Rodnan skin score (mRSS) and disease duration in dcSSc patients, as well as with digital ulcers in the whole cohort; but not with DLCO nor elevated systolic pulmonary arterial pressure (sPAP) on echocardiography. 27 According to Chighizola et al , chemerin levels were lower in dcSSc patients but similar in lcSSc patients when compared with healthy controls; and correlated with disease duration (especially in dcSSc) but not with capillaroscopic pattern, ILD or digital ulcers. 28 Sawicka et al observed higher chemerin values in SSc patients, especially among dcSSc, than in controls. 29 They were also associated with acute phase reactants in the whole cohort and with mRSS in dcSSc patients, but not with disease duration, forced vital capacity nor DLCO. 29 In summary, while no asso- ciation was identified with ILD, previous studies have reported chemerin levels in dcSSc patients as similar, lower and higher that lcSSc and healthy controls. This discrepancy is challenging to explain. It should be noted however that our work used a different design, as we deliberately constituted homogeneous
Sanges S, et al . Ann Rheum Dis 2023; 82 :365–373. doi:10.1136/ard-2022-223237
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