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MDA5 expression is associated with TGF-β-induced fibrosis: potential mechanism of interstitial lung disease in anti-MDA5 dermatomyositis.
- Source :
-
Rheumatology . Jan2023, Vol. 62 Issue 1, p373-383. 11p. - Publication Year :
- 2023
-
Abstract
- Objectives This study aimed to investigate the high-resolution CT (HRCT) characteristics of anti-melanoma differentiation-associated gene 5 (MDA5) antibody positive dermatomyositis-associated interstitial lung disease (anti-MDA5 DM-ILD), and to clarify the underlying mechanisms of the clinical phenomenon. Methods Clinical data and HRCT patterns were compared between anti-MDA5 DM-ILD (n = 32) and antisynthetase syndrome-associated ILD (ASS-ILD) (n = 29). RNA sequencing of whole-blood samples from the two groups, and in vitro experiments using human embryonic lung fibroblasts (HELFs) were conducted to explore the potential mechanisms of the clinical findings. Results The anti-MDA5 DM-ILD subset had a significantly higher incidence of rapidly progressive ILD (RPILD) than ASS-ILD (65.6% vs 37.9%; P = 0.031). The relative percentage of the lung fibrosis HRCT pattern was significantly lower in the anti-MDA5 DM-ILD group, especially the RPILD subgroup (P = 0.013 and 0.003, respectively). RNA sequencing detected the upregulated genes including interferon-induced helicase C domain 1 (encoding MDA5), and a trend towards downregulated expression of TGF-β signalling components in anti-MDA5 DM-ILD. In vitro culture of HELFs revealed that upregulated expression of MDA5 in HELFs was correlated with the downregulated expression of alpha smooth muscle actin, connective tissue growth factor, collagen I and collagen III by suppressing the TGF-β signalling pathway. Conclusions Anti-MDA5 DM-ILD patients have significantly less lung fibrosis and elevated MDA5 expression. The upregulated expression of MDA5 has relations with the suppression of the pro-fibrotic function of fibroblasts via the TGF-β signalling pathway, which may partially explain the mechanism of the clinical phenomenon. [ABSTRACT FROM AUTHOR]
- Subjects :
- *RNA analysis
*TRANSFORMING growth factors-beta
*IN vitro studies
*COLLAGEN
*DERMATOMYOSITIS
*SEQUENCE analysis
*FIBROBLASTS
*CONNECTIVE tissue growth factor
*CELL culture
*ANTISYNTHETASE syndrome
*INTERSTITIAL lung diseases
*CYTOSKELETAL proteins
*CELLULAR signal transduction
*DESCRIPTIVE statistics
*GENES
*PULMONARY fibrosis
*COMPUTED tomography
*ANTIGENS
*DISEASE risk factors
*SYMPTOMS
*DISEASE complications
*METABOLISM
Subjects
Details
- Language :
- English
- ISSN :
- 14620324
- Volume :
- 62
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Rheumatology
- Publication Type :
- Academic Journal
- Accession number :
- 160965659
- Full Text :
- https://doi.org/10.1093/rheumatology/keac234