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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.
Original languageEnglish
Pages (from-to)175-182.e5
Number of pages13
JournalCell Metabolism
Volume28
Issue number1
DOIs
Publication statusPublished - 3 Jul 2018

Keywords

  • MYOCARDIAL-INFARCTION
  • CIRCADIAN CLOCK
  • RECRUITMENT
  • LEUKOCYTE
  • CCR2
  • HYPERLIPIDEMIA
  • EXPRESSION
  • MONOCYTES
  • LY6C(HI)
  • ADHESION

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