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

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. [Display omitted] •Myeloid cells adhere to atherosclerotic lesions in a circadian fashion•Circulating myeloid cells deposit CCL2 rhythmically on the arterial endothelium•Myeloid cell adhesion patterns in macro- and microcirculation are 12 hr phase shifted•Chrono-pharmacological treatment strategy targets early atherosclerosis development 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.