Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions.
Inflammatory cytokines are well-recognized mediators of atherosclerosis. Depending on the pathological context, type I interferons (IFNs; IFNalpha and IFNbeta) exert either pro- or anti-inflammatory immune functions, but their exact role in atherogenesis has not been clarified. Here, we demonstrate that IFNbeta enhances macrophage-endothelial cell adhesion and promotes leukocyte attraction to atherosclerosis-prone sites in mice in a chemokine-dependent manner. Moreover, IFNbeta treatment accelerates lesion formation in two different mouse models of atherosclerosis and increases macrophage accumulation in the plaques. Concomitantly, absence of endogenous type I IFN signaling in myeloid cells inhibits lesion development, protects against lesional accumulation of macrophages, and prevents necrotic core formation. Finally, we show that type I IFN signaling is upregulated in ruptured human atherosclerotic plaques. Hereby, we identify type I IFNs as proatherosclerotic cytokines that may serve as additional targets for prevention or treatment.
Goossens
Pieter
P
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands.
Gijbels
Marion J J
MJ
Zernecke
Alma
A
Eijgelaar
Wouter
W
Vergouwe
Monique N
MN
van der Made
Ingeborg
I
Vanderlocht
Joris
J
Beckers
Linda
L
Buurman
Wim A
WA
Daemen
Mat J A P
MJ
Kalinke
Ulrich
U
Weber
Christian
C
Lutgens
Esther
E
de Winther
Menno P J
MP
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology*; D002448:Cell Adhesion; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000633:toxicity*; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology*; D018110:Receptors, Lipoprotein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D001057:Apolipoproteins E; C050009:IDL receptor; D018110:Receptors, Lipoprotein; D016899:Interferon-beta