Cong-Lin Liu1,2, Xin Liu2, Yuanyuan Zhang2,3, Jing Liu2, Chongzhe Yang2, Songyuan Luo2, Tianxiao Liu2, Yunzhe Wang1,2, Jes S Lindholt4,5,6, Axel Diederichsen5,7, Lars M Rasmussen5,8, Marie Dahl6, Galina K Sukhova2, Guanyi Lu9, Gilbert R Upchurch9, Peter Libby2, Junli Guo2,3, Jinying Zhang1, Guo-Ping Shi1,2. 1. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, China (C.L., Y.W., J.Z., G.-P.S.). 2. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (C.L., X.L., Y.Z., J.L., C.Y., S.L., T.L., Y.W., G.K.S., P.L., J.G., G.-P.S.). 3. Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, Key Laboratory of Emergency and Trauma of Ministry of Education, Research Unit of Island Emergency Medicine of Chinese Academy of Medical Sciences, The First Affiliated Hospital of Hainan Medical University, Haikou 571199, China (Y.Z., J.G.). 4. Department of Cardiothoracic and Vascular Surgery (J.S.L.), Odense University Hospital, Denmark. 5. Elitary Research Centre of Personalised Medicine in Arterial Disease (CIMA) (J.S.L., A.D., L.M.R.), Odense University Hospital, Denmark. 6. Cardiovascular Research Unit, Viborg Hospital, Denmark (J.S.L., M.D.). 7. Department of Cardiology (A.D.), Odense University Hospital, Denmark. 8. Department of Clinical Biochemistry and Pharmacology (L.M.R.), Odense University Hospital, Denmark. 9. Department of Surgery, University of Florida Health System, Gainesville, FL (G.L., G.R.U.).
Abstract
RATIONALE: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease. OBJECTIVE: To test whether and how eosinophils affect AAA growth. METHODS AND RESULTS: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 109/L, P<0.001). Univariate (odds ratio, 1.381, P<0.001) and multivariate (odds ratio, 1.237, P=0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in Apoe-/- and eosinophil-deficient Apoe-/-ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13-/- mice, but not eosinophil from Il4-/- mice, blocked AAA growth in Apoe-/-ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells. CONCLUSIONS: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.
RATIONALE: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease. OBJECTIVE: To test whether and how eosinophils affect AAA growth. METHODS AND RESULTS: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 109/L, P<0.001). Univariate (odds ratio, 1.381, P<0.001) and multivariate (odds ratio, 1.237, P=0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in Apoe-/- and eosinophil-deficient Apoe-/-ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13-/- mice, but not eosinophil from Il4-/- mice, blocked AAA growth in Apoe-/-ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells. CONCLUSIONS: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.
Authors: De Yang; Qian Chen; Shao Bo Su; Ping Zhang; Kahori Kurosaka; Rachel R Caspi; Suzanne M Michalek; Helene F Rosenberg; Ning Zhang; Joost J Oppenheim Journal: J Exp Med Date: 2008-01-14 Impact factor: 14.307
Authors: Christer Janson; Leif Bjermer; Lauri Lehtimäki; Hannu Kankaanranta; Jussi Karjalainen; Alan Altraja; Valentyna Yasinska; Bernt Aarli; Madeleine Rådinger; Johan Hellgren; Magnus Lofdahl; Peter H Howarth; Celeste Porsbjerg Journal: Eur Clin Respir J Date: 2022-03-02
Authors: Olesya A Puchenkova; Vladislav O Soldatov; Andrei E Belykh; OlgaYu Bushueva; Gennadii A Piavchenko; Artem A Venediktov; Nikolay K Shakhpazyan; Alexey V Deykin; Mikhail V Korokin; Mikhail V Pokrovskiy Journal: Biomark Insights Date: 2022-04-25