Bouffette Selena, Soret Perrine, Cole Alice, Nony Emmanuel, Barbier Saint Hilaire Pierre, Leclerc Grégory, Alaoui Lamine, Aussy Audrey, Wehrle Isabelle, Le Gall Aude, Coulon Mark, Pallardy Marc, Ong Voon, Allinne Jeanne, Moingeon Philippe, Abraham David, Denton Christopher P
Servier R&D Institute, Gif-sur-Yvette, France.
Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, Inserm, Orsay, France.
FEBS J. 2025 Jul 7. doi: 10.1111/febs.70177.
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.
系统性硬化症（SSc）是一种罕见的自身免疫性结缔组织疾病，其主要死亡原因是间质性肺疾病（ILD）。本研究旨在确定系统性硬化症患者中与ILD进展相关的标志物。总共纳入了52例系统性硬化症患者和5名健康志愿者（HV）。患者血浆样本可用于通过代谢组学、蛋白质组学和细胞因子定量来测量可溶性介质。对患者的全血和皮肤活检样本进行基因表达谱分析，并对外周血单核细胞进行免疫表型分析。对进展性ILD患者、无ILD患者和健康志愿者进行了比较。我们的结果证实了促炎机制参与了系统性硬化症相关的ILD，1型干扰素（IFN1）、 fractalkine（CX3CL1）和C-C基序趋化因子2（CCL2）水平升高，以及促纤维化标志物C-X-C基序趋化因子17（CXCL17）、血小板反应蛋白（THBS）和潜伏转化生长因子β结合蛋白1（LTBP1）水平升高。在细胞水平上，系统性硬化症-ILD患者的炎症活性较低，这可能是由于正在进行的免疫抑制治疗。ILD进展与血浆中细胞骨架蛋白和脂质水平显著升高有关，尤其是甘油三酯。据我们所知，这是第一项使用创新方法比较有ILD的系统性硬化症患者和无ILD的系统性硬化症患者的研究。我们的研究是在特征明确的患者中进行的，从中我们收集了有洞察力的比较数据，提供了系统性硬化症相关ILD的多层次生物学图景。我们研究的一个新发现是甘油三酯水平升高与ILD进展之间的相关性，这可能通过甘油三酯在内质网应激中的作用与纤维化有关。
