Universität zu Köln

Adam, Matti ORCID: 0000-0002-6990-8135, Kooreman, Nigel Geoffrey, Jagger, Ann, Wagenhaeuser, Markus U., Mehrkens, Dennis ORCID: 0000-0002-8578-0290, Wang, Yongming, Kayama, Yosuke, Toyama, Kensuke, Raaz, Uwe, Schellinger, Isabel N., Maegdefessel, Lars ORCID: 0000-0001-5228-2634, Spin, Joshua M., Hamming, Jaap F., Quax, Paul H. A., Baldus, Stephan, Wu, Joseph C. and Tsao, Philip S. (2018). Systemic Upregulation of IL-10 (Interleukin-10) Using a Nonimmunogenic Vector Reduces Growth and Rate of Dissecting Abdominal Aortic Aneurysm. Arterioscler. Thromb. Vasc. Biol., 38 (8). S. 1796 - 1806. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4636

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Adam, Matti UNSPECIFIED orcid.org/0000-0002-6990-8135 UNSPECIFIED Kooreman, Nigel Geoffrey UNSPECIFIED UNSPECIFIED UNSPECIFIED Jagger, Ann UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagenhaeuser, Markus U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mehrkens, Dennis UNSPECIFIED orcid.org/0000-0002-8578-0290 UNSPECIFIED Wang, Yongming UNSPECIFIED UNSPECIFIED UNSPECIFIED Kayama, Yosuke UNSPECIFIED UNSPECIFIED UNSPECIFIED Toyama, Kensuke UNSPECIFIED UNSPECIFIED UNSPECIFIED Raaz, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Schellinger, Isabel N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Maegdefessel, Lars UNSPECIFIED orcid.org/0000-0001-5228-2634 UNSPECIFIED Spin, Joshua M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamming, Jaap F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quax, Paul H. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldus, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Joseph C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tsao, Philip S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-178810
DOI:	10.1161/ATVBAHA.117.310672
Journal or Publication Title:	Arterioscler. Thromb. Vasc. Biol.
Volume:	38
Number:	8
Page Range:	S. 1796 - 1806
Date:	2018
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4636
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language E-DEFICIENT MICE; SMOOTH-MUSCLE-CELLS; II-INFUSED MICE; T-CELLS; MINICIRCLE VECTOR; ATHEROSCLEROSIS; MACROPHAGES; INHIBITION; EXPRESSION; COLITIS Multiple languages Hematology; Peripheral Vascular Disease Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17881