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

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

doi:10.1038/ncomms9523

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.

Highlights

Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases
Because miRNAs may participate in signal transduction feedback circuits by maintaining the expression of signalling proteins[23], we further evaluated the contributions of miR-142-5p and miR-130a-3p in maintaining suppressor of cytokine signalling 1 (SOCS1) and peroxisome proliferator-activated receptor g (PPARg) levels in M2 macrophages by examining the kinetics of the miRNAs and their target genes in macrophages following IL-4 treatment
Discussion miscellaneous pathological processes may lead to fibrosis, the Th2 response induced by pathogen infections, such as hepatitis viruses, and autoimmune attack, such as idiopathic pulmonary fibrosis (IPF), is a crucial link between inflammation and fibrosis[5,34]

Summary

Introduction

Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. 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. MiR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation. 7), is secreted by lung macrophages in idiopathic pulmonary fibrosis (IPF) patients and induces collagen production by fibroblasts[8,9]. IL-4/IL-13 activates the STAT6 pathway for M2 polarization, these cytokines induce negative feedback to inhibit STAT6 phosphorylation by upregulating suppressor of cytokine signalling 1 (SOCS1), which competes with STAT6 for phosphorylation binding sites of JAK2. M2 macrophages require additional mechanisms that overcome the elevated SOCS1 to maintain sufficient STAT6 phosphorylation and their perpetuation of fibrogenesis in chronic inflammatory diseases. We report that increased miR-142-5p and decreased miR-130a-3p induced by IL4/IL13 target SOCS1 and PPARg, respectively, and regulate the profibrogenesis of macrophages in chronic inflammation

Methods

Results

Conclusion