Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis.
The CXC ligand (CXCL)12/CXC receptor (CXCR)4 chemokine-receptor axis controls hematopoiesis, organ development, and angiogenesis, but its role in the inflammatory pathogenesis of atherosclerosis is unknown. Here we show that interference with Cxcl12/Cxcr4 by a small-molecule antagonist, genetic Cxcr4 deficiency, or lentiviral transduction with Cxcr4 degrakine in bone marrow chimeras aggravated diet-induced atherosclerosis in apolipoprotein E-deficient (Apoe-/-) or LDL receptor-deficient (Ldlr-/-) mice. Chronic blockade of Cxcr4 caused leukocytosis and an expansion of neutrophils and increased neutrophil content in plaques, associated with apoptosis and a proinflammatory phenotype. Whereas circulating neutrophils were recruited to atherosclerotic lesions, depletion of neutrophils reduced plaque formation and prevented its exacerbation after blocking Cxcr4. Disrupting Cxcl12/Cxcr4 thus promotes lesion formation through deranged neutrophil homeostasis, indicating that Cxcl12/Cxcr4 controls the important contribution of neutrophils to atherogenesis in mice.
Zernecke
Alma
A
Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule, Aachen University, Germany.
Bot
Ilze
I
Djalali-Talab
Yassin
Y
Shagdarsuren
Erdenechimeg
E
Bidzhekov
Kiril
K
Meiler
Svenja
S
Krohn
Regina
R
Schober
Andreas
A
Sperandio
Markus
M
Soehnlein
Oliver
O
Bornemann
Jörg
J
Tacke
Frank
F
Biessen
Erik A
EA
Weber
Christian
C
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D004032:Diet; D007249:Inflammation / Q000209:etiology; D007964:Leukocytosis / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D009503:Neutropenia; D009504:Neutrophils / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology*; D011973:Receptors, LDL / Q000172:deficiency
D001057:Apolipoproteins E; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D011973:Receptors, LDL