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

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

doi:10.1152/ajplung.00531.2016

Cited by 70 publications

(73 citation statements)

References 60 publications

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“…Under physiological conditions, Th17 and Treg are in a dynamic equilibrium. In PAH, the balance of Th17 and Treg is broken, and Th17 cells, which have proinflammatory effects, are increased, and the activation of Treg cells, which exert anti-inflammatory protective effects, is reduced [39]. Osman and colleagues found that Tregs suppressed inflammation, immune dysregulation and vascular remodeling in females and that they thereby exert a protective effect in PAH models [33].…”

Section: Discussionmentioning

confidence: 99%

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Zhu

Zhang

et al. 2020

Respir Res

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Objective: To investigate the differences in the proportions of BMPR2 mutations in familial hereditary pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH) between males and females and the relationship between BMPR2 mutation and PAH severity. Methods: A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and EMBASE databases for clinical trials containing information on the relationship between PAH prognosis and BMPR2 mutations through March 2019. After obtaining the data, a meta-analysis was performed using Review Manager Version 5.3 and Stata. Results: A meta-analysis was performed on 17 clinical trials (2198 total patients: 644 male, 1554 female). The results showed that among patients with HPAH and IPAH, the BMPR2 mutation rate is higher in male than in female patients [male group (224/644, 34.78%), female group (457/1554, 29.41%), OR = 1.30, 95% CI: 1.06~1.60, P = 0.01, I 2 = 10%]. Furthermore, haemodynamic and functional parameters were more severe in IPAH and HPAH patients with BMPR2 mutations than in those without, and those with BMPR2 mutation were diagnosed at a younger age. The risk of death or transplantation was higher in PAH patients with BMPR2 mutations than in those without (OR = 2.51, 95% CI: 1.29~3.57, P = 0.003, I 2 = 24%). Furthermore, the difference was significant only in male patients (OR = 5.58, 95% CI: 2.16~14.39, P = 0.0004, I 2 = 0%) and not in female patients (OR = 1.41, 95% CI: 0.75~2.67, P = 0.29, I 2 = 0%). Conclusion: Among patients with HPAH and IPAH, men are more likely to have BMPR2 mutations, which may predict more severe PAH indications and prognosis.

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Section: Discussionmentioning

confidence: 99%

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Zhu

Zhang

et al. 2020

Respir Res

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“…Maston et al 34 found that RAG1 −/− mice, which lack mature T and B cells, exhibited and attenuated HPH phenotype, while the adoptive transfer of CD4 + T cells or Th17 cells could restore this process. However, the role of IL-17 in PH pathology is unknown.…”

Section: Discussionmentioning

confidence: 99%

Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin

Wang

Liu

Wang

et al. 2019

Thorax

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BackgroundThe role of interleukin 17 (IL-17) in hypoxic pulmonary hypertension (HPH) remains unclear. This study is designed to explore whether IL-17 is a potential target for HPH treatment.MethodsClinic samples from the lung tissue and serum were obtained from qualified patients. Western blotting, immunohistochemistry and/or ELISA were used to measure the expression of relevant proteins. HPH models were established in C57BL/6 wild-type (WT) and IL-17 −/− mice and were treated with exogenous recombinant mouse IL-17 (rmIL-17) or an IL-17 neutralising antibody. Assays for cell proliferation, angiogenesis and adhesion were employed to analyse the behaviours of human pulmonary arterial endothelial cells (HPAECs). A non-contact Transwell coculture model was used to evaluate intercellular interactions.ResultsExpression of IL-17 was increased in lung tissue of both patients with bronchiectasis/COPD-associated PH and HPH mouse model. Compared with WT mice, IL-17 −/− mice had attenuated HPH, whereas administration of rmIL-17 aggravated HPH. In vitro, recombinant human IL-17 (rhIL-17) promoted proliferation, angiogenesis and adhesion in HPAECs through upregulation of Wnt3a/β-catenin/CyclinD1 pathway, and siRNA-mediated knockdown of β-catenin almost completely reversed this IL-17-mediated phenomena. IL-17 promoted the proliferation but not the migration of human pulmonary arterial smooth muscle cells (HPASMCs) cocultured with HPAECs under both normoxia and hypoxia, but IL-17 had no direct effect on proliferation and migration of HPASMCs. Blockade of IL-17 with a neutralising antibody attenuated HPH in WT mice.ConclusionsIL-17 contributes to the pathogenesis of HPH through upregulation of β-catenin expression. Targeting IL-17 might provide potential benefits for alternative therapeutic strategies for HPH.

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“…The cellular suspension was prepared by enzymatically digesting the lungs as previously reported. 16 Lung IL-6, sIL-6R, and sgp130 levels were normalized to total protein determined by the Bradford method (Biorad).…”

Section: Methodsmentioning

confidence: 99%

“…Pulmonary arterial remodeling was assessed using a modification of previously published methods. 16 After collection of hemodynamic data, the lungs were perfused via the RV with ∼5 mL of modified physiological saline solution (HEPES-PSS, 134 mM NaCl, 6 mM KCl, 1 mM MgCl 2 , 10 mM HEPES, 2 mM CaCl 2 , 0.026 mM EDTA, and 10 mM glucose) containing heparin, 4% albumin (Sigma), and 10 −4 M papaverine (Sigma), at 20 mmHg to maximally dilate and flush the circulation of blood. The heart, lungs, and trachea were removed in block, and the lungs inflated through the trachea with the same solution.…”

Section: Methodsmentioning

confidence: 99%

Interleukin‐6 trans‐signaling contributes to chronic hypoxia‐induced pulmonary hypertension

et al. 2018

Self Cite

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Interleukin-6 (IL-6) is a pleotropic cytokine that signals through the membrane-bound IL-6 receptor (mIL-6R) to induce anti-inflammatory (“classic-signaling”) responses. This cytokine also binds to the soluble IL-6R (sIL-6R) to promote inflammation (“trans-signaling”). mIL-6R expression is restricted to hepatocytes and immune cells. Activated T cells release sIL-6R into adjacent tissues to induce trans-signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. Reports show that IL-6 is produced by pulmonary arterial smooth muscle cells (PASMCs) exposed to hypoxia in culture as well as the medial layer of the pulmonary arteries in mice exposed to chronic hypoxia (CH), and IL-6 knockout mice are protected from CH-induced pulmonary hypertension (PH). IL-6 has the potential to contribute to a broad array of downstream effects, such as cell growth and migration. CH-induced PH is associated with increased proliferation and migration of PASMCs to previously non-muscularized vessels of the lung. We tested the hypothesis that IL-6 trans-signaling contributes to CH-induced PH and arterial remodeling. Plasma levels of sgp130 were significantly decreased in mice exposed to CH (380 mmHg) for five days compared to normoxic control mice (630 mmHg), while sIL-6R levels were unchanged. Consistent with our hypothesis, mice that received the IL-6 trans-signaling-specific inhibitor sgp130Fc, a fusion protein of the soluble extracellular portion of gp130 with the constant portion of the mouse IgG1 antibody, showed attenuation of CH-induced increases in right ventricular systolic pressure, right ventricular and pulmonary arterial remodeling as compared to vehicle (saline)-treated control mice. In addition, PASMCs cultured in the presence of IL-6 and sIL-6R showed enhanced migration but not proliferation compared to those treated with IL-6 or sIL-6R alone or in the presence of sgp130Fc. These results indicate that IL-6 trans-signaling contributes to pulmonary arterial cell migration and CH-induced PH.

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

Cited by 70 publications

References 60 publications

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin

Interleukin‐6 trans‐signaling contributes to chronic hypoxia‐induced pulmonary hypertension

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