ICAM-1 regulates macrophage polarization by suppressing MCP-1 expression via miR-124 upregulation

Abstract

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.

ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis

“…111,112 Furthermore, ICAM-1 was found to directly impact macrophage polarization and promote the pro-repair phenotype by positively modulating miR-124 expression. 113 Thus, by enhancing macrophage efferocytosis and the pro-repair reprograming, ICAM-1 can contribute to inflammatory resolution and tissue healing. ICAM-1 expressed by T cells was found to function as a co-stimulatory molecule to promote T-cell activation, 50 where activated regulatory T cells promote the pro-repair function of macrophage by increasing efferocytosis and production of IL-10.…”

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

“…Similarly, downregulation of CCL2 expression via overexpression of miR124 in RAW264.7 cells and porcine alveolar macrophages led to decreased M1 and enhanced M2 polarization without any additional stimulation, as measured by expression of M1 (iNOS, IL-6) and M2 (IL-10, MRC1, Ym1) markers. In RAW264.7 cells transfected with miR124 in the presence of LPS, the M1 phenotype could be rescued (95). Apart from Sodhi and Biswas, who confirmed that their CCL2 was endotoxin-free and showed that the effect of CCL2 stimulation could be blocked with an anti-CCR2 antibody (113), other studies cited here leave open the possibility that effects observed may be due to contaminating inflammatory stimuli such as LPS or harder to detect lipoproteins in recombinant protein preparations, or to other cellular changes caused by miR124 overexpression, and require confirmation that the effect was specific to CCL2.…”

“…Moreover, in the murine A-ZIP-Tg CCL2 knockout model, CCL2 deficiency led to reduced ERK1/2 and p38 MAPK phosphorylation (97). In a different study, Gu et al found that silencing the adhesion molecule ICAM-1, which positively modulates expression of the CCL2 mRNA binding miR124, increases CCL2 expression (95). As such, there is still a lot to uncover regarding the underlying signaling mechanisms.…”

“…Sierra-Filardi et al performed profiling of human and murine macrophages by reverse transcription PCR (RT-PCR) and fluorescence-activated cell sorting and showed that GM-CSF differentiated macrophages do express CCR2 (100). Moreover, evidence from experiments using macrophage cell lines in vitro (summarized in Table 3) show an effect of CCL2 treatment and CCL2 blocking on macrophage polarization (95,98,99,101) or anti-CCL2 treatment (101). Much evidence showing that macrophages can respond to CCL2 also comes from studies done on osteoclasts, which are tissue-resident macrophages (102)(103)(104)(105).…”

Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells

“…Regarding the role of ICAM-1 in macrophages, this also remains controversial. ICAM-1 deficiency increases M2 macrophage polarization and suppress tumor metastasis [65], but others reported that downregulation of ICAM-1 in RAW264.7 macrophages resulted in inflammatory M1 polarization [66]. Therefore, the possible implication of ICAM-1 expression in macrophages and its regulation by butyrate in periodontal tissue homeostasis remains to be determined.…”