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Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes

EMBO Mol Med (2013) 5, 1–11

Interview with: Dr. Soehnlein, Dr. Drechsler

Basic Sciences, Pharmacology, Genomics and Cardiovascular Pathology

Q: Dr. Soehnlein, Dr. Drechsler, congratulations to your recent publication in EMBO Molecular Medicine. Can you briefly summarize the rationale and key findings of the study for us?
A: Monocytes and macrophages are the most abundant white blood cell subsets in atherosclerotic lesions. To enter atherosclerotic plaques, monocytes employ specific guide cues called chemokines which induce monocyte migration via binding to chemokine receptors. However, these ligands and receptors may not just be important in emigration of monocytes from the blood to the arteries, but they may also control mobilization from the bone marrow or the life span of monocytes. Hence, the aim of this study was to investigate the importance of various chemokines and their receptors in atherogenic monocyte mobilization and recruitment.
With the existence of two murine monocyte subsets we first wanted to investigate which of these two subsets is more important in early stages of atherosclerosis. Based on a depletion and reconstitution strategy we could identify an important role for classical monocytes. Under conditions of hypercholesterolemia, a classical risk factor for atherosclerosis, classical monocytes are produced in larger numbers in the bone marrow and spleen and based on data from this study we identify that the CXCL1-CXCR2 axis is important in mobilization of classical monocytes from these sites of production. In contrast to this and to previously published data, CCR1 and CCR5 but not CCR2 or CX3CR1 were found to be important chemokine receptors mediating the accumulation of classical monocytes in atherosclerotic lesions. Collectively, the data from our study establish the impact of classical monocytes on atheroprogression, and identify a sequential role of CXCL1 in atherogenic mobilization of classical monocytes and CCR1/CCR5 in arterial recruitment of classical monocytes.

Q: You developed a novel approach for leukocyte depletion by application of a cytostatic drug. Can you describe this method and explain the reason for using this novel strategy?
A: A major aim of the study was to clearly dissect the particular function of each monocyte subset in atherosclerotic development and progression which until now has not conclusively been demonstrated. However, we faced the problem not being able to specifically deplete each subset. In a consequence, we thought of a strategy which would enable us to suppress the endogenous generation and mobilization of leukocytes in atherogenic mice by applying the cytostatic drug Cyclophosphamide (CPM) twice a week. Except for a control group, we subsequently reconstituted these animals with total leukocytes from age matched donor mice that had been depleted for either classical or non-classical monocytes by fluorescence activated cell sorting. As expected, rendering mice leukopenic led to decreased atheroprogression, whereas mice reconstituted with total leukocytes displayed atherosclerotic plaque sizes comparable to those of animals not treated with CPM. Interestingly, removal of classical monocytes but not of non-classical monocytes from donor leukocytes reduced atherosclerotic lesion area to levels observed in mice receiving CPM only. In summary, by this novel approach we were able to proof the dominant role of classical but not non-classical monocytes in atheroprogression.

Q: To conclude, can you speculate on a potential clinical relevance for therapeutic intervention?
A: Continuous influx of classical monocytes to atherosclerotic lesion sites is one of the most crucial steps in atheroprogression. Under atherogenic conditions this is mainly regulated at two different levels. First, increased numbers of classical monocytes can be observed under hyperlipidemia and numbers of circulating monocytes have been correlated to the extent of atherosclerosis in mice as well as the susceptibility for acute cardiovascular events in man. Second, monocytes have to be recruited efficiently to atherosclerotic lesions, which is partially regulated by chemokine receptors. In our study we provide evidence for the CXCL1-CXCR2 axis being involved in HFD-induced mobilization of classical monocytes. In line, blockade of CXCL1 prevented from hyperlipidemia-triggered monocytosis accompanied by reduced lesion formation. Regarding chemokine-triggered adhesion we could show that classical monocyte recruitment is primarily mediated by CCR1 and CCR5 but not CCR2 and CX3CR1 as assumed before. However, ligands for CCR1 and CCR5 such as CCL5 (Rantes) have been reported to be deposited by platelets onto atherosclerotic endothelium thereby facilitating leukocyte adhesion which is further amplified by a heteromerization of CCL5 and CXCL4. In a previous study, disruption of heteromerization led to decreased monocyte adhesion an atherosclerotic burden in mice further highlighting the significance of the CCR1/CCR5-CCL5/CXCL4 axis in arterial monocyte recruitment.
Hence, in our study we identify three potential targets for therapeutic intervention. However, further studies are warranted to dissect the specificity of such interventional strategies.

Q: What are the next steps for the future?
A: It is one of the most important findings of our study that we were able to clearly attribute pro-atherogenic effects to classical monocytes. Hence, current and future work focuses on the various mechanisms by which classical monocytes may contribute to atherosclerosis. Such include their production in the bone marrow and the spleen, their mobilization from these sites, their recruitment into large arteries, their differentiation towards the various macrophage phenotypes as well as their possible exit from atherosclerotic lesions.

Q: Dr. Soehnlein, Dr. Drechsler, thank you for your time to discuss these exciting findings with us.


Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes
EMBO Mol Med (2013) 5, 1–11

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.