The Role of Regulatory T Cells in Pulmonary Arterial Hypertension

Tian, Wen; Jiang, Shenghua; Jiang, Xinguo; Tamošiūnienė, Rasa; Kim, Dong-Eon; Guan, Torrey; Arsalane, Siham; Pasupneti, Shravani; Voelkel, Norbert F.; Tang, Qizhi; Nicolls, Mark R.

doi:10.3389/fimmu.2021.684657

Cited by 30 publications

(23 citation statements)

References 117 publications

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“…These results suggested that the targets of m6A regulators participated in the regulation of the activity of Tregs. According to previous studies, abnormal Treg function was strongly correlated with a predisposition to PAH in animal models and PAH patients ( Tian et al, 2021 ). The present study was the first one to reveal that the m6A regulators in Tregs were abnormal, and the target genes of these m6A regulators were involved in the regulation of the important biological functions of Tregs.…”

Section: Discussionmentioning

confidence: 81%

Comprehensive analysis of the expression of N6-methyladenosine RNA methylation regulators in pulmonary artery hypertension

et al. 2022

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Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling. The development of PAH involves N6-methyladenosine (m6A) modification. However, the functional role of m6A regulators in PAH and the underlying regulatory mechanisms remain unknown so far.Methods: Microarray data (GSE149713) for monocrotaline induced PAH (MCT-PAH) rat models were downloaded and screened for differentially expressed genes (DEGs) and m6A regulators. Next, we screened for differentially expressed m6A regulators in endothelial cells (ECs), smooth muscle cells (SMCs), fibroblasts, interstitial macrophages, NK cells, B cells, T cells, regulatory T cells (Tregs) using scRNA sequencing data. The target DEGs of m6A regulators in ECs, SMCs, fibroblasts, and Tregs were functionally annotated using the Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In addition, the cellular interaction analysis was performed to reveal the receptor—ligand pairs regulated by m6A regulators. Pseudo-time trajectory analyses were performed and a ceRNA network of lncRNAs-miRNAs-mRNAs was constructed in SMCs. Furthermore, the RNA transcriptome sequencing data for the SMCs isolated from idiopathic PAH (IPAH) patients (GSE144274) were validated for differentially expressed m6A regulators. Moreover, the HNRNPA2B1 levels in the lung samples from PAH patients and MCT-PAH were determined using immunohistochemistry.Results: The m6A regulators were observed to be dysregulated in PAH. HNRNPA2B1expression level was increased in the PASMCs of scRNAs and IPAH patients. The target DEGs of HNRNPA2B1 were enriched in the regulation of muscle cell differentiation and vasculature development in PASMCs. The HNRNPA2B1 expression levels determined were consistent with the proliferation-related and collagen synthesis-related gene COL4A1. Moreover, the predicted transcription factors (TFs) foxd2/3 and NFκB could be involved in the regulation of HNRNPA2B1. HNRNPA2B1 might be regulating SMCs proliferation and phenotypic transition via rno-miR-330–3p/TGFβR3 and rno-miR-125a-3p/slc39a1. In addition, HNRNPA2B1 was observed to be highly expressed in the lung samples from MCT-PAH rat models and patients with PAH.Conclusion: In summary, the present study identified certain key functional m6A regulators that are involved in pulmonary vascular remodeling. The investigation of m6A patterns might be promising and provide biomarkers for diagnosis and treatment of PAH in the future.

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Section: Discussionmentioning

confidence: 81%

Comprehensive analysis of the expression of N6-methyladenosine RNA methylation regulators in pulmonary artery hypertension

et al. 2022

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“…Restriction and downregulation of immune responses is fundamental to control inflammatory conditions and to sustain self-tolerance and is thus of particular importance in the prevention of autoinflammation and autoimmunity. To date, T regs which secret the anti-inflammatory cytokine IL-10 ( Martini et al, 2020 ; Tian et al, 2021 ) have been studied in the context of various cardiovascular diseases like atherosclerosis ( Meng et al, 2016 ) and also PH where they have beneficial effect in terms of disease progression, implying that T reg deficiency or malfunction might trigger disease aggravation ( Martini et al, 2020 ; Tian et al, 2021 ; Figure 1 ).…”

Section: Adaptive Immunitymentioning

confidence: 99%

Dysregulated Immunity in Pulmonary Hypertension: From Companion to Composer

et al. 2022

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Pulmonary hypertension (PH) represents a grave condition associated with high morbidity and mortality, emphasizing a desperate need for innovative and targeted therapeutic strategies. Cumulative evidence suggests that inflammation and dysregulated immunity interdependently affect maladaptive organ perfusion and congestion as hemodynamic hallmarks of the pathophysiology of PH. The role of altered cellular and humoral immunity in PH gains increasing attention, especially in pulmonary arterial hypertension (PAH), revealing novel mechanistic insights into the underlying immunopathology. Whether these immunophysiological aspects display a universal character and also hold true for other types of PH (e.g., PH associated with left heart disease, PH-LHD), or whether there are unique immunological signatures depending on the underlying cause of disease are points of consideration and discussion. Inflammatory mediators and cellular immune circuits connect the local inflammatory landscape in the lung and heart through inter-organ communication, involving, e.g., the complement system, sphingosine-1-phosphate (S1P), cytokines and subsets of, e.g., monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and T- and B-lymphocytes with distinct and organ-specific pro- and anti-inflammatory functions in homeostasis and disease. Perivascular macrophage expansion and monocyte recruitment have been proposed as key pathogenic drivers of vascular remodeling, the principal pathological mechanism in PAH, pinpointing toward future directions of anti-inflammatory therapeutic strategies. Moreover, different B- and T-effector cells as well as DCs may play an important role in the pathophysiology of PH as an imbalance of T-helper-17-cells (TH17) activated by monocyte-derived DCs, a potentially protective role of regulatory T-cells (Treg) and autoantibody-producing plasma cells occur in diverse PH animal models and human PH. This article highlights novel aspects of the innate and adaptive immunity and their interaction as disease mediators of PH and its specific subtypes, noticeable inflammatory mediators and summarizes therapeutic targets and strategies arising thereby.

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“…T-regs modulate immune responses and maintain tolerance to self-antigens 57 . In PAH, T-regs deficiency can lead to unchecked immune responses against self-antigens, resulting in endothelial injury and vascular remodeling 58 . In a preclinical study, T-regs-depleted athymic rats developed severe pulmonary hypertension after exposure to hypoxia 59 .…”

Section: Cytokines and Chemokinesmentioning

confidence: 99%

New Therapeutic Pathways in Pulmonary Arterial Hypertension

Ayoub¹,

Hassan²,

Hassoun³

2022

BRN

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Pulmonary arterial hypertension (PAH) is a serious and progressive vascular disease characterized by arterial vasoconstriction, remodeling, and inflammation. Despite considerable progress in the treatment of patients with PAH, long-term survival remains poor. Currently approved therapies target three well-characterized pathways involved in pulmonary vascular tone, with a poorly understood effect, if any, on vascular remodeling. Over the last two decades, novel pathways implicated in PAH remodeling and pathogenesis have been unraveled. Such pathways involve uncontrolled cellular proliferation, excessive inflammation, metabolic abnormalities, mitochondrial dysfunction, and genetic dysregulation. Several pre-clinical studies and clinical trials are currently exploring the potential benefits and safety of new therapeutic agents targeting these pathways, with the aim of modifying the disease course and improving long-term survival.

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The Role of Regulatory T Cells in Pulmonary Arterial Hypertension

Cited by 30 publications

References 117 publications

Comprehensive analysis of the expression of N6-methyladenosine RNA methylation regulators in pulmonary artery hypertension

Comprehensive analysis of the expression of N6-methyladenosine RNA methylation regulators in pulmonary artery hypertension

Dysregulated Immunity in Pulmonary Hypertension: From Companion to Composer

New Therapeutic Pathways in Pulmonary Arterial Hypertension

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