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:
CreatorsEmailORCIDORCID Put Code
Adam, MattiUNSPECIFIEDorcid.org/0000-0002-6990-8135UNSPECIFIED
Kooreman, Nigel GeoffreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jagger, AnnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagenhaeuser, Markus U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehrkens, DennisUNSPECIFIEDorcid.org/0000-0002-8578-0290UNSPECIFIED
Wang, YongmingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kayama, YosukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toyama, KensukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raaz, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schellinger, Isabel N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maegdefessel, LarsUNSPECIFIEDorcid.org/0000-0001-5228-2634UNSPECIFIED
Spin, Joshua M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamming, Jaap F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quax, Paul H. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Joseph C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsao, Philip S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
E-DEFICIENT MICE; SMOOTH-MUSCLE-CELLS; II-INFUSED MICE; T-CELLS; MINICIRCLE VECTOR; ATHEROSCLEROSIS; MACROPHAGES; INHIBITION; EXPRESSION; COLITISMultiple languages
Hematology; Peripheral Vascular DiseaseMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17881

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