Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 38, Issue 8, Pages 1796-1805Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.117.310672
Keywords
aneurysm; cytokines; interleukin; macrophages; mannose receptor; transfection
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Funding
- National Institutes of Health [R01 HL105299, R01 HL122939, R01 AI085575, R01 HL093172]
- Department of Veterans Affairs [1I01BX002641-01A]
- Deutsche Forschungsgemeinschaft [AD 492/1-1, WA 3583/2-1, RA 2179/1-1]
- Boehringer Ingelheim Fonds
- Medical School of the University Erlangen, Germany
- Banyu Life Science Foundation International
- Stanford Cardiovascular Institute
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Objective Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE(-/-) infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.110.8% (control) to 131.0 +/- 5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4(+)/CD25(+)/Foxp3 (forkhead box P3)(+) regulatory T cells, with fewer CD8(+)/GZMB(+) (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF- (tumor necrosis factor-), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.
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