Chrono-pharmacological Targeting of the CCL2-CCR2 Axis Ameliorates Atherosclerosis

Publication date: Available online 31 May 2018
Source:Cell Metabolism
Author(s): Carla Winter, Carlos Silvestre-Roig, Almudena Ortega-Gomez, Patricia Lemnitzer, Hessel Poelman, Ariane Schumski, Janine Winter, Maik Drechsler, Renske de Jong, Roland Immler, Markus Sperandio, Michael Hristov, Tanja Zeller, Gerry A.F. Nicolaes, Christian Weber, Joana R. Viola, Andres Hidalgo, Christoph Scheiermann, Oliver Soehnlein
Onset of cardiovascular complications as a consequence of atherosclerosis exhibits a circadian incidence with a peak in the morning hours. Although development of atherosclerosis extends for long periods of time through arterial leukocyte recruitment, we hypothesized that discrete diurnal invasion of the arterial wall could sustain atherogenic growth. Here, we show that myeloid cell recruitment to atherosclerotic lesions oscillates with a peak during the transition from the activity to the resting phase. This diurnal phenotype is regulated by rhythmic release of myeloid cell-derived CCL2, and blockade of its signaling abolished oscillatory leukocyte adhesion. In contrast, we show that myeloid cell adhesion to microvascular beds peaks during the early activity phase. Consequently, timed pharmacological CCR2 neutralization during the activity phase caused inhibition of atherosclerosis without disturbing microvascular recruitment. These findings demonstrate that chronic inflammation of large vessels feeds on rhythmic myeloid cell recruitment, and lay the foundation for chrono-pharmacology-based therapy.

Graphical abstract

Teaser

Winter et al. identify an oscillatory myeloid cell recruitment pattern to atherosclerotic lesions regulated, in part, by rhythmic deposition of CCL2 on arterial endothelium. These findings lay the foundation for a chrono-pharmacological treatment strategy targeting early lesion development without disturbing microvascular recruitment of myeloid cells.


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