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Abstract

During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall1,2. The observation that circulating monocytes give rise to lesional macrophages3,4,5,6,7,8,9 has reinforced the concept that monocyte infiltration dictates macrophage buildup. Recent work has indicated, however, that macrophage accumulation does not depend on monocyte recruitment in some inflammatory contexts10. We therefore revisited the mechanism underlying macrophage accumulation in atherosclerosis. In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4 weeks. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation through the involvement of scavenger receptor A (SR-A). Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease.

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Acknowledgements

We thank M. Greene for secretarial assistance. We thank J. Whitsett at Cincinnati Children's Hospital Medical Center for providing Csf2rb−/− mice. This work was supported in part by US National Institutes of Health grants 1R01HL095612 (to F.K.S.) and HHSN 268201000044C, P01-A154904, U24-CA092782 and P50-CA086355 (to R.W.) and start-up funding provided by the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research and the Department of Laboratory Medicine and Pathobiology, University of Toronto (to C.S.R.). C.S.R. was supported by the Massachusetts General Hospital Executive Committee on Research (ECOR) Postdoctoral Award. G.F.W. and I.H. were supported by the German Research Foundation. I.T. was supported by the Max Kade Foundation. L.M.S.G. was supported by the Boehringer Ingelheim Funds.

Author information

Author notes

    • Clinton S Robbins
    •  & Ingo Hilgendorf

    These authors contributed equally to this work.

Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Clinton S Robbins
    • , Ingo Hilgendorf
    • , Georg F Weber
    • , Igor Theurl
    • , Yoshiko Iwamoto
    • , Jose-Luiz Figueiredo
    • , Rostic Gorbatov
    • , Louisa M S Gerhardt
    • , Herbert Y Lin
    • , Matthias Nahrendorf
    • , Ralph Weissleder
    •  & Filip K Swirski
  2. Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.

    • Clinton S Robbins
    • , David Smyth
    • , Caleb C J Zavitz
    • , Eric A Shikatani
    •  & Mansoor Husain
  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Clinton S Robbins
    • , Eric A Shikatani
    •  & Mansoor Husain
  4. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

    • Clinton S Robbins
  5. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Jose-Luiz Figueiredo
    • , Galina K Sukhova
    •  & Peter Libby
  6. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Michael Parsons
  7. Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands.

    • Nico van Rooijen
  8. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Ralph Weissleder

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Contributions

C.S.R. and I.H. conceived the project, designed and performed experiments, and analyzed and interpreted data. G.F.W., I.T., L.M.S.G., D.S., C.C.J.Z. and E.A.S. performed experiments and helped interpret the data. J.-L.F., R.G. and I.H. performed animal surgeries. Y.I. performed the immunofluorescence histology and immunohistochemistry. M.P. performed ImageStreamX Mark II studies. G.K.S., P.L., M.N., M.H. and R.W. provided materials, intellectual input and edited the manuscript. N.v.R. provided clodronate liposomes. H.Y.L. edited the manuscript. F.K.S. conceived the project, designed experiments and supervised the study. C.S.R. and F.K.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Clinton S Robbins or Filip K Swirski.

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DOI

https://doi.org/10.1038/nm.3258

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