Interferon-gamma and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture.
BACKGROUND
Vascular disease can manifest as stenotic plaques or ectatic aneurysms, although the mechanisms culminating in these divergent disease manifestations remain poorly understood. T-helper type 1 cytokines, including interferon-gamma and CXCL10, have been strongly implicated in atherosclerotic plaque development.


RESULTS
Here, we specifically examined their role in the formation of abdominal aortic aneurysms in the angiotensin II-induced murine model. Unexpectedly, we found increased suprarenal aortic diameters, abdominal aortic aneurysm incidence, and aneurysmal death in apolipoprotein E- and interferon-gamma-deficient (Apoe(-/-)/Ifng(-/-)) mice compared with Apoe(-/-) controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-gamma-inducible T-cell chemoattractant CXCL10 was highly induced by angiotensin II infusion in Apoe(-/-) mice, but this induction was markedly attenuated in Apoe(-/-)/Ifng(-/-) mice. Apoe(-/-)/Cxcl10(-/-) mice had decreased luminal plaque but also increased aortic size, worse morphological grades of aneurysms, and a higher incidence of death due to aortic rupture than Apoe(-/-) controls. Furthermore, abdominal aortic aneurysms in Apoe(-/-)/Cxcl10(-/-) mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-beta1. Treatment of Apoe(-/-)/Cxcl10(-/-) mice with anti-transforming growth factor-beta neutralizing antibody diminished angiotensin II-induced aortic dilation.


CONCLUSIONS
The present study defines a novel pathway in which interferon-gamma and its effector, CXCL10, contribute to divergent pathways in abdominal aortic aneurysm versus plaque formation, inhibiting the former pathology but promoting the latter. Thus, efforts to develop antiinflammatory strategies for atherosclerosis must carefully consider potential effects on all manifestations of vascular disease.
King
Victoria L
VL
Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.
Lin
Alexander Y
AY
Kristo
Fjoralba
F
Anderson
Thomas J T
TJ
Ahluwalia
Neil
N
Hardy
Gregory J
GJ
Owens
A Phillip
AP
Howatt
Deborah A
DA
Shen
Dongxiao
D
Tager
Andrew M
AM
Luster
Andrew D
AD
Daugherty
Alan
A
Gerszten
Robert E
RE
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001019:Aortic Rupture / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D002316:Cardiotonic Agents; D054357:Chemokine CXCL10; D007371:Interferon-gamma