ADAM Metallopeptidase domain 19 promotes skin fibrosis in systemic sclerosis via neuregulin-1

Background: ADAM19 (ADAM Metallopeptidase Domain 19) is known to be involved in extracellular matrix (ECM) remodeling, yet its specific function in systemic sclerosis (SSc) fibrosis remains unclear.

Objectives: This study sought to clarify the role and underlying mechanism of ADAM19 in SSc skin fibrosis.

Methods: The expression of ADAM19 was assessed in skin tissues of SSc and wound healing using publicly available transcriptome datasets. This analysis was further validated through real-time PCR, western blot, and immunostaining in our SSc cohort, as well as in a mouse model of hypochlorite (HOCl)-induced fibrosis. To downregulate the expression of ADAM19, ADAM19 siRNA was employed. The influence of ADAM19 on fibroblast transcriptomics was examined using bulk RNA-seq. Data analysis and visualization were conducted using R packages, including edgeR, limma, clusterProfiler, ggplot2, gseaplot2, and complexheatmap.

Results: ADAM19 exhibited a significant upregulation in skin tissues of SSc patients, as well as in wound healing and a HOCl-induced fibrosis mouse model. Additionally, there was a notable positive correlation between ADAM19 and fibrosis-related genes, local skin score, Modified Rodnan skin score, skin thickness progression rate, and the presence of ARA antibodies in SSc patients. Furthermore, ADAM19 levels were markedly elevated in SSc primary dermal fibroblasts and TGF-β-stimulated healthy controls primary dermal fibroblasts. The downregulation of ADAM19 resulted in the repression of TGF-β-induced ECM deposition and fibroblast activation. ADAM19 was identified as a mediator for the shedding of neuregulin-1 (NRG1) in fibroblasts, a pro-fibrotic cytokine that must be cleaved to exert its function.

Conclusion: ADAM19 plays a role in TGF-β-induced ECM deposition and fibroblast activation by mediating the shedding of NRG1, ultimately contributing to the development of skin fibrosis in SSc.