Circulating interferon-γ–inducible Cys-X-Cys chemokine receptor 3 ligands are elevated in humans with aortic aneurysms and Cys-X-Cys chemokine receptor.

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Circulating interferon-γ–inducible Cys-X-Cys chemokine receptor 3 ligands are elevated in humans with aortic aneurysms and Cys-X-Cys chemokine receptor 3 is necessary for aneurysm formation in mice Amy Gallo, MD, Ahmad Saad, MD, Rahmat Ali, MD, Alan Dardik, MD, PhD, George Tellides, MD, PhD, Arnar Geirsson, MD The Journal of Thoracic and Cardiovascular Surgery Volume 143, Issue 3, Pages 704-710 (March 2012) DOI: 10.1016/j.jtcvs.2011.08.036 Copyright © 2012 Terms and Conditions

Figure 1 Schema of Th1 immune responses and the IFN-γ cytokine axis in arterial immune responses. Activation of naïve T-cell precursors, or Th0 cells, occurs in draining lymph nodes of the aorta or periadventitial tertiary lymphoid organs that organize around chronically inflamed arteries. The cytokine milieu at the time of cognate recognition of antigen skews the development of CD4+ effector T cells into different lineages characterized by the polarization of secreted cytokines, that is, IFN-γ–producing Th1 cells, IL-4–producing Th2 cells, IL-10–producing Th3 cells, and IL-17–producing Th17 cells. Recirculating T cells reach the vessel wall via the luminal endothelium or from microvessels of the adventitia and occasionally outer media of the thoracic aorta. Th1 cells preferentially express the chemokine receptor CXCR3, and their recruitment, retention, and activation are augmented by the IFN-γ–inducible CXCR3 ligands IP-10, Mig, and I-TAC that are robustly produced by vascular cells, such as medial smooth muscle cells. The positive feedback loop of IFN-γ–inducing factors, IFN-γ, and IFN-γ–inducible chemokines is referred to as the IFN-γ cytokine axis. IP-10, Interferon-inducible protein-10; I-TAC, interferon-inducible T-cell alpha chemoattractant; Mig, monokine induced by interferon gamma; SMC, smooth muscle cell; IFN, interferon; Th, T-helper; CXCR3, Cys-X-Cys chemokine receptor 3. The Journal of Thoracic and Cardiovascular Surgery 2012 143, 704-710DOI: (10.1016/j.jtcvs.2011.08.036) Copyright © 2012 Terms and Conditions

Figure 2 Circulating chemokines in serum of humans with and without aortic aneurysms. IFN-γ (A), IP-10 (B), I-TAC (C), and Mig (D) plasma levels in picograms/milliliter as measured by enzyme-linked immunosorbent assay. Values are mean ± standard error of the mean. ∗P < .001. IFN, Interferon; I-TAC, interferon-inducible T-cell alpha chemoattractant; IP-10, interferon-inducible protein-10; Mig, monokine induced by interferon gamma. The Journal of Thoracic and Cardiovascular Surgery 2012 143, 704-710DOI: (10.1016/j.jtcvs.2011.08.036) Copyright © 2012 Terms and Conditions

Figure 3 Circulating chemokines in patients with aortic aneurysms do not correlate with aneurysm diameter or growth rate. Scatter plots of IFN-γ (A, B), IP-10 (B, C), I-TAC (D, E), and Mig (F, G) plasma levels with aneurysm diameter (left) or growth rates (right). Growth rates were determined for patients with serial images (73%, n = 19). Cytokine and chemokine levels are expressed in picograms/milliliter as measured by enzyme-linked immunosorbent assay. r is the correlation coefficient calculated using Pearson correlation. IFN, Interferon; I-TAC, interferon-inducible T-cell alpha chemoattractant; IP-10, interferon-inducible protein-10; Mig, monokine induced by interferon gamma. The Journal of Thoracic and Cardiovascular Surgery 2012 143, 704-710DOI: (10.1016/j.jtcvs.2011.08.036) Copyright © 2012 Terms and Conditions

Figure 4 CXCR3−/− mice do not develop aneurysms. A, Gross photographs of aneurysm development in calcium chloride–treated right common carotid arteries versus saline-treated left common carotid arteries in WT mice at days 0, 28, and 70 (right to left); bars represent artery diameter. B, Bar graphs showing the average internal elastic lamina perimeters, external elastic lamina perimeters, and vessel area of the calcium chloride–treated (black bars) and saline-treated (white bars) carotid arteries. WT, n = 8; CXCR3−/−, n = 8. Values are mean ± standard error of the mean. ∗P < .05. C, Infiltrating CD45+ leukocytes in calcium chloride–treated versus saline-treated carotid arteries in WT and CXCR3−/− mice were detected by immunohistochemistry. Bar graphs represent the mean number of CD45+ cells per artery cross-section. WT, n = 6; CXCR3−/−, n = 5. Values are mean ± standard error of the mean. ∗P < .05. RCA, Right coronary artery; LCA, left coronary artery; IEL, internal elastic lamina; EEL, external elastic lamina; WT, wild type; CXCR3, Cys-X-Cys chemokine receptor 3. The Journal of Thoracic and Cardiovascular Surgery 2012 143, 704-710DOI: (10.1016/j.jtcvs.2011.08.036) Copyright © 2012 Terms and Conditions