Local proliferation dominates lesional macrophage accumulation in atherosclerosis.
During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall. The observation that circulating monocytes give rise to lesional macrophages 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 contexts. 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.
1] Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [4] Department of Immunology, University of Toronto, Toronto, Ontario, Canada. [5].
Clinton S
CS
Robbins
Ingo
I
Hilgendorf
Georg F
GF
Weber
Igor
I
Theurl
Yoshiko
Y
Iwamoto
Jose-Luiz
JL
Figueiredo
Rostic
R
Gorbatov
Galina K
GK
Sukhova
Louisa M S
LM
Gerhardt
David
D
Smyth
Caleb C J
CC
Zavitz
Eric A
EA
Shikatani
Michael
M
Parsons
Nico
N
van Rooijen
Herbert Y
HY
Lin
Mansoor
M
Husain
Peter
P
Libby
Matthias
M
Nahrendorf
Ralph
R
Weissleder
Filip K
FK
Swirski
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D007249:Inflammation; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology