Interferon-γ and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture

Victoria L. King, Alexander Y. Lin, Fjoralba Kristo, Thomas J.T. Anderson, Neil Ahluwalia, Gregory J. Hardy, A. Phillip Owens, Deborah A. Howatt, Dongxiao Shen, Andrew M. Tager, Andrew D. Luster, Alan Daugherty, Robert E. Gerszten

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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-γ and CXCL10, have been strongly implicated in atherosclerotic plaque development. Methods and 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-γ-deficient (Apoe-/-/Ifng -/-) mice compared with Apoe-/- controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-γ-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 -/-/Cxc110-/- 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-/-/Cxc110 -/- mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-β1. Treatment of Apoe -/-/Cxc110-/- mice with anti-transforming growth factor-β neutralizing antibody diminished angiotensin II-induced aortic dilation. Conclusions-The present study defines a novel pathway in which interferon-γ 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.

Original languageEnglish
Pages (from-to)426-435
Number of pages10
JournalCirculation
Volume119
Issue number3
DOIs
StatePublished - Jan 27 2009

Keywords

  • Aneurysm
  • Atherosclerosis
  • Immunology
  • Inflammation
  • Mice, knockout

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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