Multi-omic analysis identifies biological processes underlying progressive interstitial lung disease in systemic sclerosis.

Abstract

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder, and its primary cause of mortality is interstitial lung disease (ILD). This study aimed to identify markers in patients with SSc that are associated with ILD progression. In total, 52 SSc patients and five healthy volunteers (HVs) were included. Patient plasma samples were available for measurement of soluble mediators by metabolomics, proteomics, and cytokine quantification. Gene expression profiling was performed on patients' whole blood and skin biopsies, and immunophenotyping was carried out on peripheral blood mononuclear cells. Comparisons were made between patients with progressive ILD, those with no ILD, and HVs. Our results confirm the involvement of pro-inflammatory mechanisms in SSc-related ILD, with elevated type 1 interferon (IFN1), fractalkine (CX3CL1), and C-C motif chemokine 2 (CCL2), as well as the profibrotic markers C-X-C motif chemokine 17 (CXCL17), thrombospondin (THBS), and latent transforming growth factor beta-binding protein 1 (LTBP1). At the cellular level, lower inflammatory activity was observed in SSc-ILD patients, which may be due to ongoing immunosuppressive therapies. ILD progression is associated with a significant increase in plasma levels of cytoskeletal proteins and lipids, notably triglycerides. To our knowledge, this is the first study using an innovative approach to compare SSc patients with ILD to those without ILD. Our study was performed on well-characterized patients, from which we gathered insightful comparative data offering a multi-level biological picture of SSc-related ILD. A novel finding of our study is the correlation between elevated triglyceride levels and ILD progression, possibly linked to fibrogenesis through the role of triglycerides in endoplasmic reticulum stress.