miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program

Shicheng Su; Qiyi Zhao; Chonghua He; Di Huang; Jiang Liu; Fei Chen; Jianing Chen; Jian-You Liao; Xiuying Cui; Yunjie Zeng; Herui Yao; Fengxi Su; Qiang Liu; Shanping Jiang; Erwei Song

doi:10.1038/ncomms9523

miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program

Nat Commun. 2015 Oct 5:6:8523. doi: 10.1038/ncomms9523.

Authors

Shicheng Su^{1

2}, Qiyi Zhao³, Chonghua He^{1

2}, Di Huang^{1

2}, Jiang Liu^{1

2}, Fei Chen^{1

2}, Jianing Chen^{1

2}, Jian-You Liao¹, Xiuying Cui^{1

2}, Yunjie Zeng^{1

4}, Herui Yao^{1

2

5}, Fengxi Su^{1

2}, Qiang Liu^{1

2}, Shanping Jiang^{1

6}, Erwei Song^{1

2}

Affiliations

¹ Guangdong 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.
² Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
³ Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
⁴ Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
⁵ Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
⁶ Department of Respiratology, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Northern
Blotting, Western
Chromatin Immunoprecipitation
Down-Regulation
Electrophoretic Mobility Shift Assay
Enzyme-Linked Immunosorbent Assay
Fibroblasts / immunology
Fibroblasts / metabolism
Flow Cytometry
Gene Expression Regulation
Humans
Interleukin-13 / immunology*
Interleukin-4 / immunology*
Liver Cirrhosis / genetics
Liver Cirrhosis / immunology*
Macrophages / immunology*
Macrophages / metabolism
Mice
MicroRNAs / genetics
MicroRNAs / immunology*
PPAR gamma / metabolism
Phosphorylation
Pinocytosis
Pulmonary Fibrosis / genetics
Pulmonary Fibrosis / immunology*
Real-Time Polymerase Chain Reaction
STAT6 Transcription Factor / metabolism
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins / metabolism
Up-Regulation

Substances

Interleukin-13
MIRN130 microRNA, human
MIRN130 microRNA, mouse
MIRN142 microRNA, human
MicroRNAs
Mirn142 microRNA, mouse
PPAR gamma
SOCS1 protein, human
STAT6 Transcription Factor
STAT6 protein, human
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins
Interleukin-4