Dataset Information

Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis.

ABSTRACT: Background:Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis. Methods:Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction. Results:SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential. Conclusions:In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients.

SUBMITTER: Leleu D

PROVIDER: S-EPMC7645042 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis.

Leleu Damien D Levionnois Emeline E Laurent Paoline P Lazaro Estibaliz E Richez Christophe C Duffau Pierre P Blanco Patrick P Sisirak Vanja V Contin-Bordes Cecile C Truchetet Marie-Elise ME

Frontiers in immunology 20201023

<h4>Background</h4>Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis.<h4>Methods</h4>Ninety-six SSc p ...[more]

PMID: 33193304

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Project description:BackgroundSystemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models.MethodsThe anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-? signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated.ResultsDZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor ?1, connective tissue growth factor, tumor necrosis factor-?, interferon-?, IL-1?, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-?1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-?/Smad signaling pathway.ConclusionsDZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.

Project description:Background and aims: Systemic sclerosis (SSc) is an autoimmune, rare multisystem chronic disease that is still not well-understood aetiologically and is challenging diagnostically. In the literature, there are ever-increasing assumptions regarding the epigenetic mechanisms involved in SSc development; one of them is circulating microRNAs. Many of them regulate TLR pathways and are significant in autoimmune balance. The aim of this study was to determine profile expression of selected microRNAs in SSc patients, including miR-126, -132, -143, -145, -155, -181a, -29a and -3148, in comparison to healthy controls. Methods: Serum microRNAs were isolated from 45 patients with SSc and 57 healthy donors (HC). Additionally, SSc patients were considered in the aspect of disease subtype, including diffuse systemic sclerosis (dcSSc) and limited systemic sclerosis (lcSSc). Results: miR-3148 was detected neither in the serum of HC nor in SSc patients. All of the rest of the analyzed microRNAs, excluding miR-126, miR-29a and miR-181a, were significantly upregulated in SSc patients in comparison to HC. However, miR-181a has been revealed only in the serum of patients with lcSSc but not dcSSc. Moderate positive correlations between the transfer factor of the lung for carbon monoxide (TLCO) and miR-126 and miR-145 were observed. A significant correlation has been found between serum miR-143 level and forced vital capacity (FVC). SSc patients with FVC ≤ 70% were characterized by significantly lower levels of miR-143 compared to patients with normal FVC. Additionally, the expression of miR-132 was significantly higher in dcSSc subgroup with detected active lung lesions compared to dcSSc patients with fibrotic lesions. Patients with an early scleroderma pattern of microangiopathy seen on nailfold video-capillaroscopy (NVC) revealed higher expression of miR-155 in serum than those with a late pattern. Conclusions: The expression profile of circulating cell-free miRNAs is significantly changed in the serum of SSc patients compared to healthy individuals. Downregulation of miRNA-181a and overexpression of miR-132, miR-143, miR-145 and miR-155 in serum may be significant in SSc in the context of biomarkers.

Dataset Information

Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis.

Publications

Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis.

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