MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages
Maliheh Nazari-Jahantigh, … , Christian Weber, Andreas Schober
Maliheh Nazari-Jahantigh, … , Christian Weber, Andreas Schober
Published October 8, 2012
Citation Information: J Clin Invest. 2012;122(11):4190-4202. https://doi.org/10.1172/JCI61716.
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Research Article Cardiology

MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages

Abstract

Macrophages in atherosclerotic plaques drive inflammatory responses, degrade lipoproteins, and phagocytose dead cells. MicroRNAs (miRs) control the differentiation and activity of macrophages by regulating the signaling of key transcription factors. However, the functional role of macrophage-related miRs in the immune response during atherogenesis is unknown. Here, we report that miR-155 is specifically expressed in atherosclerotic plaques and proinflammatory macrophages, where it was induced by treatment with mildly oxidized LDL (moxLDL) and IFN-γ. Leukocyte-specific Mir155 deficiency reduced plaque size and number of lesional macrophages after partial carotid ligation in atherosclerotic (Apoe–/–) mice. In macrophages stimulated with moxLDL/IFN-γ in vitro, and in lesional macrophages, loss of Mir155 reduced the expression of the chemokine CCL2, which promotes the recruitment of monocytes to atherosclerotic plaques. Additionally, we found that miR-155 directly repressed expression of BCL6, a transcription factor that attenuates proinflammatory NF-κB signaling. Silencing of Bcl6 in mice harboring Mir155–/– macrophages enhanced plaque formation and CCL2 expression. Taken together, these data demonstrated that miR-155 plays a key role in atherogenic programming of macrophages to sustain and enhance vascular inflammation.

Authors

Maliheh Nazari-Jahantigh, Yuanyuan Wei, Heidi Noels, Shamima Akhtar, Zhe Zhou, Rory R. Koenen, Kathrin Heyll, Felix Gremse, Fabian Kiessling, Jochen Grommes, Christian Weber, Andreas Schober

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Figure 8

Role of NF-κB and TNF-α in regulating CCL2 and BCL6 expression during macrophage stimulation.

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Role of NF-κB and TNF-α in regulating CCL2 and BCL6 expression during ma...
(A and B) Role of NF-κB signaling in increased Ccl2 (A) and Tnf (B) mRNA expression in Bcl6 siRNA–treated Mir155–/– BMDMs, as determined using the NF-κB inhibitor BAY11-7085. (C) CCL2 protein levels in the medium of Mir155+/+ BMDMs after stimulation with moxLDL and IFN-γ, quantified by ELISA. A blocking antibody against TNF-α or an isotype control antibody was added to the medium. (D) CCL2 protein levels in the medium of Mir155+/+ or Mir155–/– BMDMs after stimulation with moxLDL and IFN-γ, quantified by ELISA. A blocking antibody against TNF-α (5 μg/ml) was added to the medium in both groups. (E) Effect of moxLDL and IFN-γ stimulation on Bcl6 mRNA expression in Mir155+/+ and Mir155–/– BMDMs. (F) BCL6 protein expression in unstimulated Mir155+/+ and Mir155–/– BMDMs, determined by Western blot. (G) Time course of BCL6 protein expression after moxLDL and IFN-γ stimulation of Mir155+/+ and Mir155–/– BMDMs, determined by Western blot. The intensity of the BCL6 bands relative to that of ACTB bands is expressed as a percentage of that in unstimulated BMBMs (F) or in Mir155+/+ BMDMs 6 hours after stimulation (G). Lanes in G were run on the same gel but were noncontiguous (white lines). (H) Bcl6 mRNA expression in BMDMs stimulated with moxLDL and IFN-γ after treatment with BAY11-7085 or vehicle. *P < 0.05. n = 3 independent experiments per group. Data are mean ± SEM.