Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis

Abstract

Background Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. Methods We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. Results Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 downregulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. Conclusions Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.)

Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin‐8 (CXCL8), Myeloid‐Related Protein 8/Myeloid‐Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease

“…Subsequently, these macrophages activate the inflammasome but also produce high levels of CXCL8, which results in chemoattraction and activation of neutrophils in the affected joint, clinically reflected by a gouty arthritis. These activated neutrophils form NETs that in turn lead to activation of plasmacytoid dendritic cells, which have recently been shown to be able to produce high quantities of CXCL8 (20).…”

“…Proteomic analysis was performed using surface-enhanced laser desorption ionization-time-of-flight mass spectrometry (SELDI-TOF-MS) technology (Ciphergen Biosystems) (for details, see ref. 20). Statistical analysis.…”

“…We have previously used SELDI-TOF-MS successfully to identify proteins associated with diseases in a nonhypothesis-driven manner (20,27). Given that increased circulating CXCL8 levels did not correlate with levels of cytokines such as IL-1 and TNF, which had been expected to be high, we postulated that a non-hypothesis-driven omics research approach-by measuring the proteomewould provide most efficient insights into the possible components coinciding with highest circulating levels of CXCL8.…”

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

“…A central role of platelet‐derived Cxcl4 (also known as platelet factor 4) was demonstrated in solid organs. It was shown that Cxcl4 is secreted not only by activated platelets, but also by plasmacytoid dendritic cells and fibroblasts 52, 53. These studies link megakaryocytes/platelets to proinflammatory programmes and the activation of profibrotic programmes in fibrosis.…”

Physiopathologie de la sclérodermie systémique

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