Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

Levi D. Maston, David T. Jones, Wieslawa Giermakowska, Tamara A. Howard, Judy L. Cannon, Wei Wang, Yongyi Wei, Weimin Xuan, Thomas C. Resta, Laura V. Gonzalez Bosc

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Inflammation is a prominent pathological feature in pulmonary arterial hypertension, as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension caused by chronic hypoxia. CD4+ T cells are required for initiating and maintaining inflammation, suggesting that these cells could play an important role in the pathogenesis of hypoxic pulmonary hypertension. Our objective was to test the hypothesis that CD4+ T cells, specifically the T helper 17 subset, contribute to chronic hypoxia-induced pulmonary hypertension. We compared indices of pulmonary hypertension resulting from chronic hypoxia (3 wk) in wild-type mice and recombination– activating gene 1 knockout mice (RAG1-/-, lacking mature T and B cells). Separate sets of mice were adoptively transferred with CD4+, CD8+, or T helper 17 cells before normoxic or chronic hypoxic exposure to evaluate the involvement of specific T cell subsets. RAG1-/- mice had diminished right ventricular systolic pressure and arterial remodeling compared with wild-type mice exposed to chronic hypoxia. Adoptive transfer of CD4+ but not CD8+ T cells restored the hypertensive phenotype in RAG1-/- mice. Interestingly, RAG1-/- mice receiving T helper 17 cells displayed evidence of pulmonary hypertension independent of chronic hypoxia. Supporting our hypothesis, depletion of CD4+ cells or treatment with SR1001, an inhibitor of T helper 17 cell development, prevented increased pressure and remodeling responses to chronic hypoxia. We conclude that T helper 17 cells play a key role in the development of chronic hypoxia-induced pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)L609-L624
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume312
Issue number5
DOIs
StatePublished - May 2017
Externally publishedYes

Keywords

  • CD4 T cells
  • Inflammation
  • Interleukin-6
  • Retinoid-related orphan receptor-γα
  • SR1001

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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