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Eosinophils Protect Mice from Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm

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  • Cong-Lin Liu, The First Affiliated Hospital of Zhengzhou University, Brigham and Women's Hospital and Harvard Medical School, Boston
  • ,
  • Xin Liu, Brigham and Women's Hospital and Harvard Medical School, Boston
  • ,
  • Yuanyuan Zhang, Brigham and Women's Hospital and Harvard Medical School, Boston, Hainan Medical University
  • ,
  • Jing Liu, Brigham and Women's Hospital and Harvard Medical School, Boston
  • ,
  • Chongzhe Yang, Brigham and Women's Hospital and Harvard Medical School, Boston
  • ,
  • Songyuan Luo, Brigham and Women's Hospital and Harvard Medical School, Boston
  • ,
  • Tianxiao Liu, Brigham and Women's Hospital and Harvard Medical School, Boston
  • ,
  • Yunzhe Wang, The First Affiliated Hospital of Zhengzhou University, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
  • ,
  • Jes S Lindholt
  • Axel Cosmus Pyndt Diederichsen, Odense University Hospital
  • ,
  • Lars Melholt Rasmussen, Odense University Hospital
  • ,
  • Marie Dahl
  • Galina K Sukhova, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
  • ,
  • Guanyi Lu, University of Florida Health System
  • ,
  • Gilbert Upchurch, University of Florida Health System
  • ,
  • Peter Libby, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
  • ,
  • Junli Guo, Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Hainan Medical University
  • ,
  • Jin-Ying Zhang, Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Hainan Medical University
  • ,
  • Guo-Ping Shi, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

RATIONALE: Blood eosinophil (EOS) count and EOS cationic protein (ECP) associate with human cardiovascular diseases (CVD). Yet, whether EOS play a role in CVD remains untested. The current study detected EOS accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting EOS participation in this aortic disease.

OBJECTIVE: To test whether and how EOS affect AAA growth.

METHODS AND RESULTS: Population-based randomized clinically controlled screening trials revealed higher blood EOS count in 579 male AAA patients than in 5,063 non-AAA control (0.236{plus minus}0.182 vs 0.211{plus minus}0.154, 109/L, P<0.001). Univariate (OR=1.381, P<0.001) and multivariate (OR=1.237, P=0.031) logistic regression analyses indicated that increased blood EOS count in AAA patients served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected EOS accumulation and EOS cationic protein expression in human and murine AAA lesions. Results showed that EOS deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell (SMC) loss using angiotensin-II perfusion-induced AAA in Apoe-/- and EOS-deficient Apoe-/-;∆dblGATA mice. EOS deficiency increased lesion chemokine expression, muted lesion expression of IL4 and EOS-associated-ribonuclease-1 (mEar1, human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, EOS-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of EOS from WT and Il13-/- mice, but not EOS from Il4-/- mice, blocked AAA growth in Apoe-/- ∆dblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for EOS IL4 and mEar1 in blocking NF-κB activation in macrophages, SMCs, and endothelial cells.

CONCLUSIONS: EOS 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.

OriginalsprogEngelsk
TidsskriftCirculation research
Vol/bind128
Nummer2
Sider (fra-til)188–202
Antal sider15
DOI
StatusUdgivet - jan. 2021

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