2. Academic Validation
  3. Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice

Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice

  • J Exp Med. 2018 Aug 6;215(8):2175-2195. doi: 10.1084/jem.20171767.
Guilin Chen 1,  Shengkai Zuo 1,  Juan Tang 2,  Caojian Zuo 3,  Daile Jia 3,  Qian Liu 2,  Guizhu Liu 2,  Qian Zhu 3,  Yuanyang Wang 1 2,  Jian Zhang 1 2,  Yujun Shen 1 2,  Dongrui Chen 4,  Ping Yuan 5,  Zhiqiang Qin 6,  Chengchao Ruan 4,  Jue Ye 7,  Xiao-Jian Wang 7,  Yuping Zhou 7,  Pingjin Gao 4,  Peng Zhang 5,  Jinming Liu 5,  Zhi-Cheng Jing 8,  Ankang Lu 3,  Ying Yu 9 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4 Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 6 National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, China.
  • 7 Thrombosis and Vascular Medicine Center, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 8 Key Laboratory of Pulmonary Vascular Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 9 Department of Pharmacology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China [email protected].
PMID: 29970474 DOI: 10.1084/jem.20171767
Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin-induced PAH in CRTH2-/- mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.

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