Paper of the Month

July 2018

Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metabolism (2018), DZHK authors: Winter, Silvestre-Roig, Ortega-Gomez, Schumski, Drechsler, Immler, Sperandio, Zeller, Weber, Viola, Soehnlein

The internal clock regulates all vital functions in the body including body temperature, blood pressure, and the release of certain hormones. Besides such physiological circadian oscillations, also disease manifestations can accumulate at a certain time of the day. In the context of cardiovascular diseases, acute coronary events predominantly occur in the morning hours, i.e. between 7 and 11 am.  Based on such epidemiologic finding, a team led by DZHK Professor Oliver Soehnlein studied how the arterial recruitment of leukocytes, a process critically determining atheroprogression, is controlled by the circadian clock.

In a mouse model of atherosclerosis the researchers showed that the adhesion on and recruitment into the arterial wall shows striking circadian oscillations: in the morning hours 3 times as many myeloid cells were recruited as compared to the evening hours. This effect is controlled by the rhythmic release of CCL2 from myeloid cells, which is immobilized on endothelial cells and consequently triggers firm leukocyte arrest. Interestingly, the peak in microvascular myeloid cell recruitment was found to be 12-hours phase-shifted. This opened a therapeutic window of opportunity, permitting the timed delivery of a CCR2 antagonist to hinder arterial leukocyte adhesion with limited interference in the microvasculature. In this study this principle was successfully tested in a mouse model of atherosclerosis.

This study was in part funded by a DZHK 'Säule B' grant (cooperation with DZHK Professor Tanja Zeller). This study also represents a continuation of earlier findings of the Soehnlein Team, where they have identified novel therapeutic means to counteract arterial myeloid cell recruitment (e.g. Alard et al., Sci Transl Med, 2015; Ortega-Gomez et al., Circulation, 2016).