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MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages

Interview with Dr. A. Schober
Basic Sciences, Pharmacology, Genomics and Cardiovascular Pathology

Q: Dr. Schober, in this month’s print issue of the Journal of Clinical Investigation you are describing a novel microRNA (miR)-155-dependent pathway in macrophages that plays a role in atherosclerosis. What are the key results of this study?

A: We found that miR-155 is specifically expressed in atherosclerotic plaques and proinflammatory macrophages. This miRNA primes macrophages for inflammatory activation by increasing the expression of CCL2. Accordingly, we demonstrated that genetic miR-155 deficiency in macrophages substantially reduces lesion formation in a mouse model of advanced atherosclerosis and increases the expression of CCL2 in lesional macrophages. Therefore, we believe that miR-155 is a key regulator of the inflammatory macrophage reprogramming, which maintains and amplifies vascular inflammation during atherosclerosis.

Q: You used a mouse model of flow-mediated atherosclerosis to confirm the relevance of miR-155 in atherosclerosis. Can you tell us more about this model?

A: Atherosclerosis is closely linked to disturbed flow characterized by low and oscillatory wall shear stress. Partial carotid ligation is an animal model in which blood flow and thus shear stress are acutely reduced. We performed partial carotid ligation in Apoe-/- mice fed a high-cholesterol diet, which are very well known to develop atherosclerosis, and studied lesion formation after 6 weeks in the carotid artery. The disturbed flow causes endothelial dysfunction and leads to advanced atherosclerotic lesion formation in combination with diet-induced hyperlipidemia. We could even show by micro-CT angiography that these carotid lesions are highly stenotic.

Q: Your in situ hybridization experiments revealed that the majority of plaque macrophages express miR-155, but also some SMA-positive cells. Could miR-155 play a role in vascular smooth muscle cells?

A: You are absolutely right. MiR-155 is not solely expressed in macrophages but we also detected miR-155 expression in smooth muscle cells of the carotid lesions. To address the role of miR-155 in vascular cells, we studied atherosclerosis in miR-155-/- which express miR-155 in macrophages. However, there was no significant difference in lesion formation in these mice compared with control mice. Therefore, only the absence of miR-155 in bone marrow cells limited atherosclerosis and miR-155 expression in smooth muscle cells does not seem to be involved in atherosclerosis.

Q: You looked more closely into the regulation of pro-inflammatory macrophage activation by miR-155. What did you find?

A: We found that miR-155 suppresses its target BCL6, which is known to inhibit the transcription of CCL2 (MCP-1) and to act as an antagonist of the pro-inflammatory transcription factor NF-B. Although several other miR-155 targets, such as SOCS1 or PU.1, were also repressed by miR-155, only targeting of BCL6 markedly enhanced the inflammatory response. In macrophages that do not express miR-155, increased levels of BCL6 limit the production of the inflammatory mediators CCL2 and TNF-alpha. The suppression of BCL6 by miR-155 plays an important role during the early phase of macrophage activation, while inflammatory stimulation triggers a negative feedback loop in which NF-kB induces BCL6, which may contribute to the termination of the inflammatory response. Moreover, we could confirm that increased BCL6 expression causes the diminished lesion formation and reduced CCL2 expression in lesional macrophages in mice with miR-155-/- macrophages by silencing BCL6 in the lesions of these mice.

Q: The finding that BCL6 is a new player in atherogenic macrophage activation is very interesting. What is known about this transcription factor?

A: BCL6 (proto-oncogene B-cell lymphoma 6) is known for its role in B-cell differentiation and B-cell lymphomas. However, BCL-6 is expressed in many different cell types and BCL-6-/- mice develop a multiorgan inflammatory response which has been attributed to the excessive production of inflammatory mediators by macrophages. BCL6 counteracts the activation of NF-B by transcriptional repression of NF-B-target genes or inhibiting the NF-B pathway itself. Recently, a key athero-protective role of BCL6 expression in macrophages on atherosclerosis has also been demonstrated by Barish et al. using atherosclerosis-prone mice harboring BCL-6-/- bone marrow cells.

Q: Could your results have clinical relevance? Should we target miRNAs for the treatment of atherosclerosis, and how?

A: This is a very interesting question. I believe that targeting of miRNAs to treat atherosclerosis is definitely a strategy that should be evaluated clinically. It has been demonstrated already by Kathryn Moore’s group that inhibition of the miRNA-33, which plays an important role in lipid metabolism, by subcutaneous administration of chemically modified antisense oligonucleotides is effective in non-human primates. We are awaiting the results of further clinical studies of anti-miR-33 therapy. The enhanced stability of the various forms of chemically modified antisense miRNAs promises to overcome the technologically demanding delivery of siRNA-based therapeutics. The availability of the antisense miRNA targeting would make it theoretically possible to inhibit any miRNA. Moreover, increasing the effects of miRNAs might be even as therapeutically important as the inhibition of miRNAs, because miRNAs also have protective effects in atherosclerosis. However, up to now the technology for treatment with miRNA mimics is still an unresolved issue.

Q: What further investigations should be performed in this area?

A: Regarding the role of miR-155 in atherosclerosis, it needs to be determined how miR-155 affects different stages of atherosclerosis. The group from Menno de Winther has recently shown that the absence of miR-155 expression in hematopoietic cells can increase diet-induced early atherosclerosis in mice, although the mechanism is unclear. To resolve these conflicting results, we are currently studying the effect of miR-155 in different stages of atherosclerosis. Moreover, in my opinion the role of the miR-155 passenger strand miR-155* needs to be addressed, since miR-155* is also induced in activated macrophages and can oppose the effects of miR-155 at least in dendritic cells.

Q: Dr. Schober, thank you very much for your time to discuss this outstanding work.



Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z, Koenen RR, Heyll K, Gremse F, Kiessling F, Grommes J, Weber C, Schober A.
J Clin Invest. 2012;122(11):4190-202
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.