Interferon-γ and the Interferon-Inducible Chemokine CXCL10 Protect Against Aneurysm Formation and Rupture

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-␥ 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-␥-deficient (Apoe Ϫ/Ϫ /Ifng Ϫ/Ϫ ) mice compared with Apoe Ϫ/Ϫ controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-␥-inducible T-cell chemoattractant CXCL10 was highly induced by angiotensin II infusion in Apoe Ϫ/Ϫ mice, but this induction was markedly attenuated in Apoe Ϫ/Ϫ /Ifng Ϫ/Ϫ mice. Apoe Ϫ/Ϫ /Cxcl10 Ϫ/Ϫ 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 Ϫ/Ϫ controls. Furthermore, abdominal aortic aneurysms in Apoe Ϫ/Ϫ /Cxcl10 Ϫ/Ϫ mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-␤1. Treatment of Apoe Ϫ/Ϫ /Cxcl10 Ϫ/Ϫ mice with anti-transforming growth factor-␤ neutralizing antibody diminished angiotensin II-induced aortic dilation. Conclusions-The present study defines a novel pathway in which interferon-␥ 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. Key Words: aneurysm Ⅲ atherosclerosis Ⅲ immunology Ⅲ inflammation Ⅲ mice, knockout T he pathophysiological mechanisms that lead to stenotic plaques versus aneurysms, 2 distinct vascular lesions, remain poorly understood. Clinically, abdominal aortic aneurysms (AAAs) are more strongly correlated with a family history 1 and smoking 2 than are coronary stenoses. Diabetes mellitus, a strong risk factor for coronary plaques, actually protects against AAA formation in population-based studies. 3,4 Clinical Perspective p 435Chronic inflammation of the vascular wall is believed to contribute to both manifestations of arterial pathology. 5,6 Atherosclerotic plaques are marked primarily by intimal infiltration of macrophages and T cells, at least at earlier disease stages. In contrast, aneurysmal segments are characterized by macrophage, T-cell, and B-cell accumulation primarily in the media and adventitia at all stages of disease evolution. 6 Human atherosclerotic stenoses specifically express mediators characteristic of a T-helper type 1 (Th1) immune response, including interferon (IFN)-␥, as well as the IFN-␥-inducible T-cell chemoattractant IP-10 (IFN-␥-inducible Protein...

TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice

“…Our results may seem to contradict recent results by King et al (21), who showed that administration of an anti-TGF-β antibody did not alter AAA development in Apoe −/− mice. Unfortunately, the authors presented no data regarding the efficiency of their neutralization protocol.…”

T lymphocytes and aortic aneurysms

“…Shimizu et al [34] found that IFN-γ receptor-deficient (GRKO) mice had an increased incidence of aneurysm formation and spontaneous rupture, thereby implying the protective role of IFN-γ in aneurysms. Similar to these findings, King et al [35] confirmed the protective role of IFN-γ in aneurysms. They suggested that IFN-γ deficiency (IFN-γ  ) led to increased incidence of AAAs in Ang II treated apolipoprotein E deficient (ApoE  ) mice.…”

TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

“…Even this may need to be qualified. While Wang and colleagues concede that another study failed to see worsening of aneurysms in TGFbNAb-treated Ang II-infused mice, they do not comment upon the fact that this study found that TGFbNAb afforded significant protection from Ang II-induced inflammatory aneurysms after Cxcl10 targeting - an event that accentuated aneurysm incidence and severity and death (23). It should also be noted that ARBs or silencing of expression of AT1R have been definitively shown to prevent Ang II-induced aneurysm in rodent models (24)(25)(26)(27)(28).…”