oncotarget-08-111882.pdf (5.1 MB)
ICAM-1 regulates macrophage polarization by suppressing MCP-1 expression via miR-124 upregulation
journal contributionposted on 2018-06-19, 00:00 authored by Wei Gu, Lun Yao, Lexing Li, Jianping Zhang, Aaron T. Place, Richard D. Minshall, Guoquan Liu
Intercellular adhesion molecule-1 is the adhesion molecule mediating leukocyte firm adhesion to endothelial cells, plays a critical role in subsequent leukocyte transmigration. ICAM-1 is also expressed in other cells including macrophages; however, the role of this adhesion molecule in mediating macrophage functions remains enigmatic. We report that ICAM-1 regulates macrophage polarization by positively modulating miR-124 expression. We found higher expression levels of monocyte chemotactic protein-1 in lungs of mice lacking ICAM-1. Consistent with this result, siRNA mediated depletion of ICAM-1 in macrophage resulted in increased expression levels of MCP-1. Moreover, ICAM-1 controlled miR-124 expression and downregulated MCP-1 mRNA and protein expression by binding of miR-124 to MCP-1 3’ untranslated region. ICAM-1 also induced the transcription factor Sp1 expression, which is important for miR-124 expressing in macrophages. Furthermore, ICAM-1 depletion led to M1 macrophage polarization, in contrast, miR-124 mimics promoted M2 macrophage polarization. Exogenous administration of miR-124 mimics into the lungs prevented lipopolysaccharide-induced myeloperoxidase activity in vivo, suggesting that miR-124 is important for dampening acute lung injury. These results collectively show that adhesion molecule ICAM-1 downregulates MCP-1 expression by controlling Sp1 mediated miR-124 levels, which in turn regulate M2 macrophage polarization. Targeting ICAM-1 and downstream miR-124 may present a new therapeutic strategy for acute lung injury.
The work is supported by National Natural Science Foundation of China (NSFC) (No. 31372418, GL.), Huazhong Agricultural University Scientific & Technology Self-innovation Foundation (program No. 2012RC011, G.L.), the 948 Project of Chinese Ministry of Agriculture (2015-Z33, GL). NIH grants RO1 HL71626 and P01 HL60678 (RM). We thank Dr. S. Reddy, University of Illinois at Chicago, for critical reading of the manuscript.
CitationGu, W., Yao, L., Li, L., Zhang, J., Place, A. T., Minshall, R. D. and Liu, G. ICAM-1 regulates macrophage polarization by suppressing MCP- 1 expression via miR-124 upregulation. Oncotarget. 2017. 8(67): 111882-111901. 10.18632/oncotarget.22948.