Local proliferation dominates lesional macrophage accumulation in atherosclerosis

Clinton S. Robbins; Ingo Hilgendorf; Georg F. Weber; Igor Theurl; Yoshiko Iwamoto; Jose Luiz Figueiredo; Rostic Gorbatov; Galina K. Sukhova; Louisa M.S. Gerhardt; David Smyth; Caleb C.J. Zavitz; Eric A. Shikatani; Michael Parsons; Nico Van Rooijen; Herbert Y. Lin; Mansoor Husain; Peter Libby; Matthias Nahrendorf; Ralph Weissleder; Filip K. Swirski

doi:10.1038/nm.3258

Local proliferation dominates lesional macrophage accumulation in atherosclerosis

Clinton S. Robbins
, Ingo Hilgendorf
, Georg F. Weber
, Igor Theurl
, Yoshiko Iwamoto
, Jose Luiz Figueiredo
, Rostic Gorbatov
, Galina K. Sukhova
, Louisa M.S. Gerhardt
, David Smyth
, Caleb C.J. Zavitz
, Eric A. Shikatani
, Michael Parsons
, Nico Van Rooijen
, Herbert Y. Lin
, Mansoor Husain
, Peter Libby
, Matthias Nahrendorf
, Ralph Weissleder
, Filip K. Swirski

Research output: Contribution to journal › Article › peer-review

922 Scopus citations

Abstract

During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall^1,2. The observation that circulating monocytes give rise to lesional macrophages ^3-9 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.

Original language	English
Pages (from-to)	1166-1172
Number of pages	7
Journal	Nature Medicine
Volume	19
Issue number	9
DOIs	https://doi.org/10.1038/nm.3258
State	Published - Sep 2013
Externally published	Yes

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Robbins, C. S., Hilgendorf, I., Weber, G. F., Theurl, I., Iwamoto, Y., Figueiredo, J. L., Gorbatov, R., Sukhova, G. K., Gerhardt, L. M. S., Smyth, D., Zavitz, C. C. J., Shikatani, E. A., Parsons, M., Van Rooijen, N., Lin, H. Y., Husain, M., Libby, P., Nahrendorf, M., Weissleder, R., & Swirski, F. K. (2013). Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nature Medicine, 19(9), 1166-1172. https://doi.org/10.1038/nm.3258

@article{f7dba8e8d3964643b7a328998e72674c,

title = "Local proliferation dominates lesional macrophage accumulation in atherosclerosis",

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 macrophages 3-9 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.",

author = "Robbins, \{Clinton S.\} and Ingo Hilgendorf and Weber, \{Georg F.\} and Igor Theurl and Yoshiko Iwamoto and Figueiredo, \{Jose Luiz\} and Rostic Gorbatov and Sukhova, \{Galina K.\} and Gerhardt, \{Louisa M.S.\} and David Smyth and Zavitz, \{Caleb C.J.\} and Shikatani, \{Eric A.\} and Michael Parsons and \{Van Rooijen\}, Nico and Lin, \{Herbert Y.\} and Mansoor Husain and Peter Libby and Matthias Nahrendorf and Ralph Weissleder and Swirski, \{Filip K.\}",

note = "Funding Information: We thank M. Greene for secretarial assistance. We thank J. Whitsett at Cincinnati Children{\textquoteright}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.",

year = "2013",

month = sep,

doi = "10.1038/nm.3258",

language = "English",

volume = "19",

pages = "1166--1172",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "9",

}

Robbins, CS, Hilgendorf, I, Weber, GF, Theurl, I, Iwamoto, Y, Figueiredo, JL, Gorbatov, R, Sukhova, GK, Gerhardt, LMS, Smyth, D, Zavitz, CCJ, Shikatani, EA, Parsons, M, Van Rooijen, N, Lin, HY, Husain, M, Libby, P, Nahrendorf, M, Weissleder, R & Swirski, FK 2013, 'Local proliferation dominates lesional macrophage accumulation in atherosclerosis', Nature Medicine, vol. 19, no. 9, pp. 1166-1172. https://doi.org/10.1038/nm.3258

TY - JOUR

T1 - Local proliferation dominates lesional macrophage accumulation in atherosclerosis

AU - Robbins, Clinton S.

AU - Hilgendorf, Ingo

AU - Weber, Georg F.

AU - Theurl, Igor

AU - Iwamoto, Yoshiko

AU - Figueiredo, Jose Luiz

AU - Gorbatov, Rostic

AU - Sukhova, Galina K.

AU - Gerhardt, Louisa M.S.

AU - Smyth, David

AU - Zavitz, Caleb C.J.

AU - Shikatani, Eric A.

AU - Parsons, Michael

AU - Van Rooijen, Nico

AU - Lin, Herbert Y.

AU - Husain, Mansoor

AU - Libby, Peter

AU - Nahrendorf, Matthias

AU - Weissleder, Ralph

AU - Swirski, Filip K.

N1 - Funding Information: 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.

PY - 2013/9

Y1 - 2013/9

N2 - 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 macrophages 3-9 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.

AB - 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 macrophages 3-9 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.

UR - https://www.scopus.com/pages/publications/84883800208

U2 - 10.1038/nm.3258

DO - 10.1038/nm.3258

M3 - Article

C2 - 23933982

AN - SCOPUS:84883800208

SN - 1078-8956

VL - 19

SP - 1166

EP - 1172

JO - Nature Medicine

JF - Nature Medicine

IS - 9

ER -

Local proliferation dominates lesional macrophage accumulation in atherosclerosis

Abstract

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