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Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2018
- Publisher :
- Rockefeller University Press, 2018.
-
Abstract
- Th2 response is implicated in the pathogenesis of PAH. Chen et al. demonstrate that CRTH2-mediated Th2 activation is exaggerated in patients with PAH and mouse PAH models, and pharmacological inhibition of CRTH2 attenuates experimental PAH by suppression of IL-4 and IL-13.<br />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.
- Subjects :
- Male
0301 basic medicine
Adoptive cell transfer
Indoles
Receptors, Prostaglandin
Blood Pressure
030204 cardiovascular system & hematology
Lymphocyte Activation
Mice
0302 clinical medicine
Bone Marrow
polycyclic compounds
Immunology and Allergy
Receptors, Immunologic
Hypoxia
Receptor
Lung
Research Articles
Chemistry
Adoptive Transfer
Up-Regulation
medicine.anatomical_structure
Interleukin 13
Female
Adult
Ovalbumin
Hypertension, Pulmonary
T cell
Immunology
Pulmonary Artery
Article
Antibodies
03 medical and health sciences
Th2 Cells
Immune system
medicine
Animals
Humans
Pyrroles
Interleukin 4
Cell Proliferation
Chimera
Cell growth
Immunity
medicine.disease
Pulmonary hypertension
Disease Models, Animal
030104 developmental biology
Chronic Disease
Cancer research
STAT6 Transcription Factor
Gene Deletion
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 215
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....c19b65a694481e05b11ca11354b65099