Chemokines and microRNAs in atherosclerosis

Abstract

The crucial role of chemokines in the initiation and progression of atherosclerosis has been widely recognized. Through essential functions in leukocyte recruitment, chemokines govern the infiltration with mononuclear cells and macrophage accumulation in atherosclerotic lesions. Beyond recruitment, chemokines also provide homeostatic functions supporting cell survival and mediating the mobilization and homing of progenitor cells. As a new regulatory layer, several microRNAs (miRNAs) have been found to modulate the function of endothelial cells (ECs), smooth muscle cells and macrophages by controlling the expression levels of chemokines and thereby affecting different stages in the progression of atherosclerosis. For instance, the expression of CXCL1 can be down-regulated by miR-181b, which inhibits nuclear factor-κB activation in atherosclerotic endothelium, thus attenuating the adhesive properties of ECs and exerting early atheroprotective effects. Conversely, CXCL12 expression can be induced by miR-126 in ECs through an auto-amplifying feedback loop to facilitate endothelial regeneration, thus limiting atherosclerosis and mediating plaque stabilization. In contrast, miR-155 plays a pro-atherogenic role by promoting the expression of CCL2 in M1-type macrophages, thereby enhancing vascular inflammation. Herein, we will review novel aspects of chemokines and their regulation by miRNAs during atherogenesis. Understanding the complex cross-talk of miRNAs controlling chemokine expression may open novel therapeutic options to treat atherosclerosis.

Fig. 1

The chemokine–miRNA interactome: a classification of chemokines according to their miRNA-regulation pattern. Black lines are indicating experimentally validated interactions of miRNAs within the 3′ UTR region of murine chemokine or chemokine receptor transcripts using the web tool DIANA-TarBase v7.0 [109]. Chemokines/chemokine receptors without validated miRNA interactions have not been included in the interactome. The size of the circles in orange (chemokines) or red (chemokine receptors) corresponds to the number of predicted miRNA-binding sites in the 3′ UTR of the respective transcripts. A substantial number of putative miRNA-binding sites is predicted for CXCL12, which is in accordance with a high number of experimentally validated miRNA–CXCL12 interactions. In fact, a striking majority (53 %) of all validated miRNA interactions among all chemokines were observed for CXCL12 alone. In contrast, a limited number of miRNA interactions is predicted for other chemokines such as CCL2 or CXCL1 and for chemokine receptors, in accordance with a low number of functionally validated miRNA-binding sites for those transcripts

Fig. 2

miRNAs control inflammatory response in ECs. miRNAs control the expression of inflammatory chemokines such as CCL2 and CXCL1 predominantly indirectly by regulating the expression of signaling molecules of the NF-κB signaling pathway. For instance, miR-181b inhibits the NF-κB-mediated CXCL1 expression by suppressing the expression of importin-α3, which is required for the nuclear translocation of NF-κB. miR-103 and miR-92a targets the NF-κB inhibitor KLF4, thereby increasing CCL2 and CXCL1 expression in ECs. In contrast, miR-21 reduces CCL2 expression by blocking the AP-1 signaling pathway. A direct regulation of CCL2 is reported for miR-495, which induces CCL2 mRNA degradation by binding to its response element in the 3′ UTR. Moreover, miR-126-3p controls the expression of CXCL12, directly and indirectly via its target RGS16. NF-κB nuclear factor-κB, CCL2 chemokine (CC motif) ligand 2, CXCL1 chemokine (CXC motif) ligand 1, CXCL12 chemokine (CXC motif) ligand 12, CXCR4 chemokine (CXC motif) receptor 4, KLF2/4 Krüppel-like factor 2/4, SOCS1 suppressor of cytokine signaling 1, β‐TRC β‐transducin repeat‐containing gene, TAK1 transforming growth factor β-activated kinase 1, TRAF6 TNF receptor-associated factor 6, IRAK1 interleukin-1 receptor-associated kinase 1/2, RGS16 regulator of G-protein signaling 16, SIRT1 sirtuin-1, THBS1 thrombospondin 1, TGFBR1 transforming growth factor, beta receptor 1, SMAD2 SMAD family member 2, PPARα peroxisome proliferator-activated receptor α, AP-1 activator-protein 1. The dashed arrow indicates an indirect regulation

Fig. 3

miRNA-mediated CCL2 expression in macrophages. The expression of CCL2 is induced by the miR-155-mediated suppression of the NF-κB inhibitor BCL6. miR-155 is regulated by miR-342-5p, which targets AKT-1 and BMPR2. miR-146 acts as a negative regulator to reduce the CCL2 expression by targeting TLR4. Moreover, CCL2 expression is triggered by the expression of CHI3L1 and LPL, which is negatively regulated by miR-24 and miR-467a, respectively. KLF2 expression in macrophages reduces the expression of CCL2 by reducing miR-150, which negatively regulates miR-124a. miR-124a directly suppresses the expression of CCL2 via its binding site in the 3′ UTR of the CCL2 mRNA transcript. NF-κB nuclear factor-κB, CCL2 chemokine (CC motif) ligand 2, BCL6 B-cell lymphoma 6, AKT1 v-akt murine thymoma viral oncogene homolog 1, BMPR2 bone morphogenetic protein receptor type II, TLR4 toll-like receptor 4, TRAF6 TNF receptor-associated factor 6, IRAK1 interleukin-1 receptor-associated kinase 1/2, CHI3L1 chitinase 3-like 1, LPL lipoprotein lipase, KLF2 Krüppel-like factor 2. The dashed arrow indicates an indirect regulation