Gu Wei, Yao Lun, Li Lexing, Zhang Jianping, Place Aaron T, Minshall Richard D, Liu Guoquan
Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province 430070, P.R. China.
Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Oncotarget. 2017 Dec 5;8(67):111882-111901. doi: 10.18632/oncotarget.22948. eCollection 2017 Dec 19.
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 , 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.
细胞间黏附分子-1是介导白细胞与内皮细胞牢固黏附的黏附分子，在随后的白细胞跨膜迁移中起关键作用。ICAM-1也在包括巨噬细胞在内的其他细胞中表达；然而，这种黏附分子在介导巨噬细胞功能中的作用仍不清楚。我们报告ICAM-1通过正向调节miR-124的表达来调节巨噬细胞极化。我们发现在缺乏ICAM-1的小鼠肺中单核细胞趋化蛋白-1的表达水平更高。与该结果一致，siRNA介导的巨噬细胞中ICAM-1的缺失导致MCP-1表达水平增加。此外，ICAM-1通过miR-124与MCP-1 3'非翻译区的结合来控制miR-124的表达并下调MCP-1的mRNA和蛋白表达。ICAM-1还诱导转录因子Sp1的表达，这对于巨噬细胞中miR-124的表达很重要。此外，ICAM-1的缺失导致M1巨噬细胞极化，相反，miR-124模拟物促进M2巨噬细胞极化。将miR-124模拟物外源性给药至肺中可预防脂多糖诱导的髓过氧化物酶活性，表明miR-124对于减轻急性肺损伤很重要。这些结果共同表明黏附分子ICAM-1通过控制Sp1介导的miR-124水平来下调MCP-1表达，进而调节M2巨噬细胞极化。靶向ICAM-1和下游的miR-124可能为急性肺损伤提供一种新的治疗策略。
