Interleukin-32 in systemic sclerosis, a potential new biomarker for pulmonary arterial hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc), associated with a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. Due to unspecific symptoms, the diagnosis of PAH is often delayed. On this basis, it is of great value to improve current diagnostic methods and develop new strategies for evaluating patients with suspected PAH. Interleukin-32 (IL-32) is a proinflammatory cytokine expressed in damaged vascular cells, and the present study aimed to assess if this cytokine could be a new biomarker of PAH during SSc. Methods: The IL-32 expression was evaluated in the sera and skin samples of 18 SSc-PAH patients, 21 SSc patients without PAH, 15 patients with idiopathic PAH (iPAH) and 14 healthy controls (HCs), by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). Receiver-operating characteristic (ROC) curves were performed to evaluate the cutoff of IL-32 in identifying patients with PAH. Furthermore, in SSc patients, correlation analyses were performed between IL-32 sera levels and mean pulmonary artery pressure (mPAP) evaluated by right heart catheterization (RHC) and systolic pulmonary artery pressure (sPAP), obtained by echocardiography. Additionally, the number of skin IL-32+ cells was correlated with modified Rodnan skin score (mRSS). Results: In SSc-PAH patients, IL-32 sera levels were significantly higher when compared with SSc patients without PAH and patients affected by iPAH. The analysis of ROC curve showed that IL-32 sera levels above 11.12 pg/ml were able to predict patients with PAH (sensitivity = 90%, specificity = 100%). Furthermore, the IL-32 sera levels of patients with SSc correlated with both mPAP and sPAP. In the skin derived from SSc-PAH patients, the number of IL-32+ cells was significantly increased when compared with the skin derived from SSc patients without PAH, correlating with the mRSS. Conclusion: Our study suggested that sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients and together with longitudinal future studies could help to increase the understanding how these biomarkers mirror the vascular changes and the inflammatory process during SSc.

Retracted: CD248 as a novel therapeutic target in pulmonary arterial hypertension

“…PDGF‐plasma levels have been found to significantly increase in patients with systemic SSc 38 . PAH is a serious complication of SSc, and is accompanied with increased expression of proinflammatory cytokine such as IL‐32 39 . Blocking of the PDGF‐BB/PDGFR‐β signaling pathway reversed the vascular remodeling in an experimental PAH model system 14 .…”

Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis

“…[37] Cells from patient-samples also differentially express pro-inflammatory cytokines such IL-32, IL-26, IL-16, which are up-regulated in the serum and in the lesional skin of SSc patients. [38][39][40] These cytokines have been implicated in the pathogenesis of other inflammatory skin diseases [41][42][43][44] by promoting secretion of other inflammatory cytokines (TNFa, IL6) and chemokines (IL8, CXCL2) by macrophages and by acting as chemoattractants and modulators of T-cell activation. Single-cell trajectory analysis indicates that SSc CD4 + and CD8 + T RM cells are distributed throughout pseudotime, while SSc T MM are mostly found in late pseudotime, indicating distinct gene expression.…”

Endothelial-to-mesenchymal transition in systemic sclerosis

“…ECs lining injuries are the early events occurring in patients with SSc [152,153]. In these patients, arteries are generally impaired and characterized by intimal hyperplasia, medial thickening, obliteration of the lumen and inflammation [58,154], thus contributing to the vascular remodelling occurring during PAH [155]. It has been reported that EndMT may also play a pivotal role during the PAH pathogenesis, promoting dysfunction of the ECs [156].…”