Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA

  • Eur Respir J. 2023 Mar 2;61(3):2200582. doi: 10.1183/13993003.00582-2022.
Ting Shu  1  2 ,  Jiawei Zhang  1  2 ,  Yitian Zhou  1  3 ,  Zhihua Chen  4 ,  Jinqiu Li  5 ,  Qihao Tang  1 ,  Wenqi Lei  1 ,  Yanjiang Xing  5  6 ,  Jing Wang  7  6 ,  Chen Wang  1  5
Affiliations
  • 1. State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Dept of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2. These authors contributed equally to this manuscript.
  • 3. MD Program, Peking Union Medical College, Beijing, China.
  • 4. Key Laboratory of Respiratory Disease of Zhejiang Province, Dept of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5. State Key Laboratory of Medical Molecular Biology, Dept of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
  • 6. J. Wang and Y. Xing contributed equally to this article as lead authors and supervised the work.
  • 7. State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Dept of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China [email protected].
PMID: 36423907 DOI: 10.1183/13993003.00582-2022
Abstract

Background: Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear.

Methods: EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1-deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments.

Results: There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating Peroxisome Proliferator-activated Receptor γ and blunting STAT3 phosphorylation.

Conclusions: In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA.

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