TY - JOUR
T1 - Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension
AU - Maston, Levi D.
AU - Jones, David T.
AU - Giermakowska, Wieslawa
AU - Howard, Tamara A.
AU - Cannon, Judy L.
AU - Wang, Wei
AU - Wei, Yongyi
AU - Xuan, Weimin
AU - Resta, Thomas C.
AU - Gonzalez Bosc, Laura V.
N1 - Funding Information:
We thank Eliseo Castillo for technical advice. Some of the images in this paper were aquired in the University of New Mexico & Cancer Center Fluorescence Microscopy Shared Resource and funded as detailed at the following link: http://hsc.unm.edu/crtc/microscopy/acknowledgement.shtml. This study was supported by Grants F30-HL-123109 [National Heart, Lung, and Blood Institute(NHLBI)] to L. D. Maston, AHA 15GRNT25090038 to L. V. Gonzalez Bosc, T32-HL-007736, R01-HL-88192 (both NHLBI), and AHA 13GRNT14510041 to T. C. Resta, R01-AI-097202 to J. L. Cannon, and NSF CHE-1565085 to W. Wang.
Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
KW - CD4 T cells
KW - Inflammation
KW - Interleukin-6
KW - Retinoid-related orphan receptor-γα
KW - SR1001
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U2 - 10.1152/ajplung.00531.2016
DO - 10.1152/ajplung.00531.2016
M3 - Article
C2 - 28213473
AN - SCOPUS:85018768990
VL - 312
SP - L609-L624
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 5
ER -