• An Erratum to this article was published on 18 May 2017

This article has been updated

Abstract

Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells. In mice infected with the intracellular pathogen Chlamydia muridarum, blood monocytes disseminated infection to the intima. Subsequent CCL19-CCR7–dependent RTM was critical for the clearance of intimal C. muridarum. This process was inhibited by hypercholesterolemia. Thus, RTM protects the normal arterial intima, and compromised RTM during atherogenesis might contribute to the intracellular retention of pathogens in atherosclerotic lesions.

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Change history

  • 20 March 2017

    In the version of this article initially published, the label along the horizontal axis of the graph in Figure 1a ('Dose (mg)') is incorrect. The correct label is 'Dose (μg)'. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank P. Lesnik (University of Pierre and Marie Curie) for CD11c–hBcl-2 mice; M.C. Nussenzweig (The Rockefeller University) for CD11c-eYFP mice; S. Nunes de Vasconcelos (Toronto General Research Institute) for Rag1−/− mice; J. Gommerman (University of Toronto) for Nos2−/− mouse bones; and N. van Rooijen (Vrije Universiteit) for CLs and PLs. Supported by the Canadian Institutes of Health Research (MOP-84446, MOP-106522 and MOP-89740 to M.I.C.).

Author information

Affiliations

  1. Toronto General Research Institute, University Health Network, Toronto, Canada.

    • Mark Roufaiel
    • , Allan Siu
    • , Su-Ning Zhu
    • , Andrew Lau
    • , Hisham Ibrahim
    • , Marwan Althagafi
    • , Kelly Tai
    • , Sharon J Hyduk
    • , Kateryna O Cybulsky
    • , Sherine Ensan
    • , Angela Li
    • , Rickvinder Besla
    • , Henry M Becker
    • , Haiyan Xiao
    • , Clinton S Robbins
    • , Jenny Jongstra-Bilen
    •  & Myron I Cybulsky
  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.

    • Mark Roufaiel
    • , Allan Siu
    • , Hisham Ibrahim
    • , Marwan Althagafi
    • , Rickvinder Besla
    • , Henry M Becker
    • , Clinton S Robbins
    • , Jenny Jongstra-Bilen
    •  & Myron I Cybulsky
  3. Krembil Research Institute, University Health Network, Toronto, Canada.

    • Eric Gracey
    •  & Robert D Inman
  4. Department of Immunology, University of Toronto, Toronto, Canada.

    • Eric Gracey
    • , Kelly Tai
    • , Sherine Ensan
    • , Angela Li
    • , Henry M Becker
    • , Robert D Inman
    • , Clinton S Robbins
    • , Jenny Jongstra-Bilen
    •  & Myron I Cybulsky
  5. Center for Immunity and Infection Lausanne, Department of Biochemistry, University of Lausanne, Switzerland.

    • Sanjiv A Luther
  6. Department of Medicine, University of Toronto, Toronto, Canada.

    • Robert D Inman

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Contributions

M.R. designed and performed most of the experiments, analyzed the data and contributed to writing the manuscript; E.G. and R.D.I. contributed to experiments with C. muridarum; A.S. and M.A. performed BrdU assays; S.-N.Z. performed ex vivo cannulation and perfusion of the aorta; A. Lau performed TUNEL staining and analysis; H.I. imaged live aortas ex vivo; K.T. performed qPCR analysis of mRNA in the intima; S.J.H. and K.O.C. contributed to function-blocking antibody experiments; S.E., A. Li and R.B. contributed to flow-cytometry sorting studies; H.M.B. contributed to the experimental design and editing; H.X. performed mouse husbandry; S.A.L. provided intellectual input and Ccl19−/− BM; C.S.R. provided intellectual input and contributed to flow-cytometry sorting studies; J.J.-B. contributed to the experimental design, project supervision and writing of the manuscript; and M.I.C. provided overall project supervision, including oversight of experiments and writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Myron I Cybulsky.

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DOI

https://doi.org/10.1038/ni.3564

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