Non-classical circulating monocytes expressing high levels of microsomal prostaglandin E2 synthase-1 tag an aberrant IFN-response in systemic sclerosis

Villanueva-Martin, Gonzalo; Acosta-Herrera, Marialbert; Carmona, Elio G.; Kerick, Martin; Ortego-Centeno, Norberto; Callejas-Rubio, Jose Luis; Mages, Norbert; Klages, Sven; Börno, Stefan; Timmermann, Bernd; Bossini-Castillo, Lara; Martin, Javier

doi:10.1016/j.jaut.2023.103097

Cited by 6 publications

(4 citation statements)

References 86 publications

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“…While the overall gene expression differences were highly correlated between SSc and GERD, there were sets of genes disproportionately upregulated in SSc that hint at disease-related immune response aberrations, including genes that have previously been implicated in SSc pathogenesis. For example, PTGES , which encodes prostaglandin E synthase, was previously found to be significantly upregulated in SSc fibroblasts 93 and inflammatory non-classical monocytes 94 , and Ptges-null mice were resistant to bleomycin-induced fibrosis 93 . CD44 and CD74 form the receptor complex for the macrophage inhibitory factor (MIF), an inflammatory cytokine that promotes fibroblast migration and has been implicated in SSc pathogenesis 95 .…”

Section: Discussionmentioning

confidence: 99%

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

Dapas,

Clevenger,

Makinde

et al. 2024

Preprint

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Systemic sclerosis (SSc) is a rare autoimmune disease characterized by vasculopathy and progressive fibrosis of the skin and internal organs. Individuals with SSc often suffer from chronic acid reflux and dysphagia due to loss of esophageal motility. However, the pathogenesis of esophageal dysmotility in SSc is poorly understood. To determine whether distinct changes in esophageal epithelial cells contribute to impaired motility in SSc, we investigated the stratified squamous esophageal epithelium using single-cell RNA sequencing (n=306,372 cells) in individuals with SSc compared those with gastroesophageal reflux disease (GERD) as well as healthy controls. The proportion of epithelial cells in the outermost, superficial compartment of the esophageal epithelium was significantly reduced in SSc (9.4% vs 21.6% in HCs). Differential gene expression in SSc was primarily limited to the superficial compartment (3,572 genes vs. 232 in all other compartments), with significant upregulation of extracellular matrix and keratinization genes. These cellular and molecular changes in SSc were highly correlated with those seen in GERD, indicating they were secondary to reflux; however, their magnitudes were more pronounced in the proximal esophagus, suggesting that esophageal dysmotility leads to greater proximal acid exposure, which may contribute to aspiration. SSc-specific gene dysregulation implicated immunoregulatory pathways likely pertinent to pathogenic mechanisms. By offering a comprehensive view of transcriptional dysregulation at single-cell resolution in human esophageal epithelial cells in SSc compared to GERD and healthy tissue, this work clarifies the state of epithelial cells in SSc-induced esophageal dysfunction.

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Section: Discussionmentioning

confidence: 99%

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

Dapas,

Clevenger,

Makinde

et al. 2024

Preprint

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“…In skin biopsies, the expression levels of TGF-β1, TGF-βR1 and TGF-βR2 are higher in SSc patients than in healthy subjects [134][135][136][137][138][139][140]. Cutaneous gene expression of macrophage-associated biomarkers (CD14, IL-13RA1) and TGF-β-associated biomarkers (OSMR SERPINE1, CTGF) is associated with cutaneous disease progression in SSc [134][135][136][137][138][139][140]. Marginal zone protein B1 (MZB1) appears to be a good biomarker for cutaneous fibrosis [116][117][118][119].…”

Section: Biomarkers In Systemic Sclerosis Skin Involvementmentioning

confidence: 99%

“…Sirtuins are NAD-dependent protein deacetylases that regulate angiogenesis; SIRT1 and SIRT3 correlate with the degree of cutaneous fibrosis of the SSc [116][117][118][119]. Adiponectin is reduced in skin affected by SSc [134][135][136][137][138][139][140]. The fibrillar collagen molecule COL4A1, the matricellular protein COMP, the gene encoding spondin-SPON1, and TNC, another ECM protein, have recently been upregulated in the skin of SSc individuals, and all these molecules completely distinguish the normal-skinned SSc [116][117][118][119].…”

Section: Biomarkers In Systemic Sclerosis Skin Involvementmentioning

confidence: 99%

“…The fibrillar collagen molecule COL4A1, the matricellular protein COMP, the gene encoding spondin-SPON1, and TNC, another ECM protein, have recently been upregulated in the skin of SSc individuals, and all these molecules completely distinguish the normal-skinned SSc [116][117][118][119]. Other investigators found that the upregulated genes IL-13RA1, OSMR and SERPINE 1 were the most predictive of progressive skin disease [134][135][136][137][138][139][140].…”

Section: Biomarkers In Systemic Sclerosis Skin Involvementmentioning

confidence: 99%

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Biomarkers in Systemic Sclerosis: An Overview

Di Maggio,

Confalonieri,

Salton

et al. 2023

CIMB

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Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor β (TGF-β) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

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The intervention of macrophages in progressive fibrosis characterizing systemic sclerosis: A systematic review

Campitiello,

Soldano,

Gotelli

et al. 2024

Autoimmunity Reviews

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Non-classical circulating monocytes expressing high levels of microsomal prostaglandin E2 synthase-1 tag an aberrant IFN-response in systemic sclerosis

Cited by 6 publications

References 86 publications

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

Biomarkers in Systemic Sclerosis: An Overview

The intervention of macrophages in progressive fibrosis characterizing systemic sclerosis: A systematic review

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