Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension

Tamošiūnienė, Rasa; Manouvakhova, Olga; Mésange, Paul; Saito, Toshie; Qian, Jin; Sanyal, Mrinmoy; Lin, Yu-Chun; Nguyen, Linh P.; Luria, Amir; Tu, Allen B.; Sante, Joshua M.; Rabinovitch, Marlene; Fitzgerald, Desmond J.; Graham, Brian B.; Habtezion, Aida; Voelkel, Norbert F.; Aurelian, Laure; Nicolls, Mark R.

doi:10.1161/circresaha.117.312058

Cited by 109 publications

(87 citation statements)

References 66 publications

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“…In addition, treatment with Ang II promotes vascular adhesion and migration of leukocytes, which can be abolished through treatment with 17β estradiol and exacerbated by incubation with l ‐ N G ‐nitroarginine methyl ester . Moreover, coculture with Treg cells induces the up‐regulation of ERα and ERβ in human cardiac microvascular ECs and increases culture supernatant concentrations of plasma prostacyclin and IL‐10 . In female PSGL‐1 −/− mice, the reduction in the percentage of Treg cells could explain why the pulmonary levels of ERα were not increased with aging, declining at the same time as the phosphorylation of eNOS and NO production.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

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Objective Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and noncurative treatments. As mice deficient in P‐selectin glycoprotein ligand 1 (PSGL‐1) develop a spontaneous SSc‐like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved. Methods Doppler echocardiography was used to estimate pulmonary pressure, immunohistochemistry was used to assess vascular remodeling, and myography of dissected pulmonary artery rings was used to analyze vascular reactivity. Angiotensin II (Ang II) levels were quantified by enzyme‐linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT1R), AT2R, endothelial cell nitric oxide synthase (eNOS), and phosphorylated eNOS expression in lung lysates. Flow cytometry allowed us to determine cytokine production by immune cells and NO production by endothelial cells. In all cases, there were 4–8 mice per experimental group. Results PSGL‐1−/− mice showed lung vessel wall remodeling and a reduced mean ± SD expression of pulmonary AT2R (expression ratio [relative to β‐actin] in female mice age >18 months: wild‐type mice 0.799 ± 0.508 versus knockout mice 0.346 ± 0.229). With aging, female PSGL‐1−/− mice had impaired up‐regulation of estrogen receptor α (ERα) and developed lung vascular endothelial dysfunction coinciding with an increase in mean ± SEM pulmonary Ang II levels (wild‐type 48.70 ± 5.13 pg/gm lung tissue versus knockout 78.02 ± 28.09 pg/gm lung tissue) and a decrease in eNOS phosphorylation, leading to reduced endothelial NO production. These events led to a reduction in the pulmonary artery acceleration time:ejection time ratio in 33% of aged female PSGL‐1−/− mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon‐γ–producing PSGL‐1−/− T cells and B cells and a reduced presence of regulatory T cells. Conclusion The absence of PSGL‐1 induces a reduction in Treg cells, NO production, and ERα expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.

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Section: Discussionmentioning

confidence: 99%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

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“…The primary study to date examining checkpoint PD-L1 expression, mainly by endothelial cells, suggests that inhibition reverses protection conferred by functional Treg adoptive transfer, fully replicating the phenotype of severe PH associated with Treg deficiency, in the SU5416 and chronic hypoxia rat model. 16 The chronic hypoxia model is, of course, severely limited in replicating the pathology of human PAH. However, the model is helpful in recapitulating key components of pulmonary hypertensive lung changes, such as immune cell oxidative stress, endothelial cell injury, and a distinct type of pulmonary inflammatory response.…”

Section: To the Editormentioning

confidence: 99%

A checkpoint on innate myeloid cells in pulmonary arterial hypertension

Bryant

et al. 2019

Pulm. circ.

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“…None of these changes were evident in PAH female rats. The less pronounced inflammatory changes in PAH females were recently associated with the increased functionality of regulatory T cell (Treg) [16]. The ability of T regs to suppress over-activation of the immune system, inflammation, and perivascular infiltration of pulmonary vessels with inflammatory cells protects females against PAH.…”

Section: Introductionmentioning

confidence: 99%

“…Although sex-mediated effects are classically viewed through the prism of sex hormones, the last research [16] and a few other recent reports [17] suggest the presence of non-hormonal mechanisms that are responsible for manifestation of the sex difference. Therefore, in this study, we were interested in investigating whether pulmonary endothelial cells omitted from the effects of sex hormones or interactions with other cell types will still preserve the sex difference.…”

Section: Introductionmentioning

confidence: 99%

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

et al. 2020

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Women are known to be associated with a higher susceptibility to pulmonary arterial hypertension (PAH). In contrast, male PAH patients have a worse survival prognosis. In this study, we investigated whether the contribution of sex goes beyond the effects of sex hormones by comparing the ability of isolated male and female pulmonary endothelial cells to respire, proliferate and tolerate the stress. Mouse lung endothelial cells (MLEC) were isolated from the lungs of male and female 3-week old mice. Male MLEC showed an increased basal mitochondrial respiration rate, elevated maximal respiration, a significantly greater level of mitochondrial polarization, and a higher rate of proliferation. Exposure of cells to hypoxia (2% of O 2 for 24 hours) induced a strong apoptotic response in female but not male MLEC. In contrast, treatment with mitochondrial respiratory Complex III inhibitor Antimycin A (AA, 50μM) mediated severe necrosis specifically in male MLEC, while female cells again responded primarily by apoptosis. The same effect with female cells responding to the stress by apoptosis and male cells responding by necrosis was confirmed in starved pulmonary endothelial cells isolated from human donors. Elevated necrosis seen in male cells was associated with a significant release of damage-associated alarmin, HMGB1. No stimuli induced a significant elevation of HMGB1 secretion in females. We conclude that male cells appear to be protected against mild stress conditions, such as hypoxia, possibly due to increased mitochondrial respiration. In contrast, they are more sensitive to impaired mitochondrial function, to which they respond by necrotic death. Necrosis in male vascular cells releases a significant amount of HMGB1 that could contribute to the pro-inflammatory phenotype known to be associated with the male gender.

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Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension

Abstract: In 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

Cited by 109 publications

References 66 publications

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

A checkpoint on innate myeloid cells in pulmonary arterial hypertension

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

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