miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program
Shicheng Su1,2, Qiyi Zhao3, Chonghua He1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Abstract:
Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARγ, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation.
Insights
MicroRNAs regulate macrophage fibrogenesis in chronic inflammation. Inhibiting miR-142-5p and boosting miR-130a-3p reduced fibrosis in mouse models and human disease.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Macrophages are crucial in fibrogenesis, a process central to chronic inflammatory diseases.
- MicroRNAs (miRNAs) are key regulators of immune cell function, but their specific roles in macrophage-driven fibrogenesis remain unclear.
Purpose of the Study:
- To investigate the role of specific microRNAs in regulating macrophage profibrogenic activity.
- To determine if modulating microRNA expression can impact tissue fibrosis.
Main Methods:
- Analyzed microRNA expression (miR-142-5p and miR-130a-3p) in macrophages stimulated with IL-4 and IL-13.
- Utilized in vitro assays to assess the impact of microRNAs on signaling pathways (STAT6, SOCS1, PPARγ).
- Employed locked nucleic acid-modified oligonucleotides to inhibit miR-142-5p and upregulate miR-130a-3p in mouse models of liver and lung fibrosis.
Main Results:
- IL-4 and IL-13 induced miR-142-5p and downregulated miR-130a-3p in macrophages, sustaining profibrogenic effects.
- miR-142-5p targets SOCS1, prolonging STAT6 phosphorylation; miR-130a-3p inhibition relieves suppression of PPARγ.
- In vivo inhibition of miR-142-5p and increased miR-130a-3p expression significantly reduced liver and lung fibrosis in mice.
- Macrophages from patients with liver cirrhosis and idiopathic pulmonary fibrosis showed altered miR-142-5p and miR-130a-3p expression.
Conclusions:
- miR-142-5p and miR-130a-3p are critical regulators of macrophage profibrogenic gene expression in chronic inflammation.
- Targeting these microRNAs offers a potential therapeutic strategy for fibrotic diseases.
