Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice

Author:

Liu Cong-Lin12ORCID,Ren Jingyuan23,Wang Yunzhe12,Zhang Xian2,Sukhova Galina K2ORCID,Liao Mengyang2,Santos Marcela2,Luo Songyuan2ORCID,Yang Dafeng2,Xia Mingcan4,Inouye Karen5,Hotamisligil Gökhan S5,Lu Guanyi6ORCID,Upchurch Gilbert R6,Libby Peter2,Guo Junli278,Zhang Jinying1,Shi Guo-Ping12ORCID

Affiliation:

1. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Zhengzhou 450052, China

2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA

3. Department of Hypertension, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China

4. Division of Allergy & Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA

5. Department of Genetics and Complex Diseases, Sabri Ülker Center for Metabolic Research, Harvard TH Chan School of Public Health, Harvard University, Boston, MA 02115, USA

6. Department of Surgery, University of Florida Health System, Gainesville, FL 32611, USA

7. Institute of Cardiovascular Research, the First Affiliated Hospital, Hainan Medical University, Haikou 571199, China

8. Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou 571199, China

Abstract

Abstract Aims Obesity is a risk factor of abdominal aortic aneurysm (AAA). Inflammatory cytokine interleukin-18 (IL18) has two receptors: IL18 receptor (IL18r) and Na-Cl co-transporter (NCC). In human and mouse AAA lesions, IL18 colocalizes to its receptors at regions rich in adipocytes, suggesting a role of adipocytes in promoting IL18 actions in AAA development. Methods and results We localized both IL18r and NCC in human and mouse AAA lesions. Murine AAA development required both receptors. In mouse AAA lesions, IL18 binding to these receptors increased at regions enriched in adipocytes or adjacent to perivascular adipose tissue. 3T3-L1 adipocytes enhanced IL18 binding to macrophages, aortic smooth muscle cells (SMCs), and endothelial cells by inducing the expression of both IL18 receptors on these cells. Adipocytes also enhanced IL18r and IL18 expression from T cells and macrophages, AAA-pertinent protease expression from macrophages, and SMC apoptosis. Perivascular implantation of adipose tissue from either diet-induced obese mice or lean mice but not that from leptin-deficient ob/ob mice exacerbated AAA development in recipient mice. Further experiments established an essential role of adipocyte leptin and fatty acid-binding protein 4 (FABP4) in promoting IL18 binding to macrophages and possibly other inflammatory and vascular cells by inducing their expression of IL18, IL18r, and NCC. Conclusion Interleukin-18 uses both IL18r and NCC to promote AAA formation. Lesion adipocyte and perivascular adipose tissue contribute to AAA pathogenesis by releasing leptin and FABP4 that induce IL18, IL18r, and NCC expression and promote IL18 actions.

Funder

Finance Science and Technology Projects of Hainan Province

National Natural Science Foundation of China

University-College Joint Cultivation Fund of Zhengzhou University

National Institute of Health

American Heart Association

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine

Reference23 articles.

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