Regulatory T Cell-Related Gene Indicators in Pulmonary Hypertension

Abstract

Objective: Regulatory T cells (Tregs) are critical immune modulators to maintain immune homeostasis and limit pulmonary hypertension (PH). This study was aimed to identify Treg-related genes (TRGs) in PH.Methods: The gene expression profile from lungs of PH patients was retrieved from the Gene Expression Omnibus (GEO) database. The abundance of Tregs was estimated by the xCell algorithm, the correlation of which with differentially expressed genes (DEGs) was performed. DEGs with a |Pearson correlation coefficient| >0.4 were identified as TRGs. Functional annotation and the protein–protein interaction (PPI) network were analyzed. A gene signature for 25 hub TRGs (TRGscore) was generated by a single sample scoring method to determine its accuracy to distinguish PH from control subjects. TRGs were validated in datasets of transcriptional profiling of PH cohorts and in lung tissues of experimental PH mice.Results: A total of 819 DEGs were identified in lungs of 58 PAH patients compared to that of 25 control subjects of dataset GSE117261. In total, 165 of all these DEGs were correlated with the abundance of Tregs and identified as TRGs, with 90 upregulated genes and 75 downregulated genes compared to that of control subjects. The upregulated TRGs were enriched in negative regulation of multiple pathways, such as cAMP-mediated signaling and I-kappaB kinase/NF-kappaB signaling, and regulated by multiple genes encoding transcriptional factors including HIF1A. Furthermore, 25 hub genes categorized into three clusters out of 165 TRGs were derived, and we identified 27 potential drugs targeting 10 hub TRGs. The TRGscore based on 25 hub TRGs was higher in PH patients and could distinguish PH from control subjects (all AUC >0.7). Among them, 10 genes including NCF2, MNDA/Ifi211, HCK, FGR, CSF3R, AQP9, S100A8, G6PD/G6pdx, PGD, and TXNRD1 were significantly reduced in lungs of severe PH patients of dataset GSE24988 as well as in lungs of hypoxic PH mice compared to corresponding controls.Conclusion: Our finding will shed some light on the Treg-associated therapeutic targets in the progression of PH and emphasize on TRGscore as a novel indicator for PH.

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

“…Immune infiltration analysis is to weigh the immune related genes in the gene expression matrix to get the activity status of related immune cells and pathways, which can be used to demonstrate relation of interested genes and immune status. The xCell R package was used to perform analysis, and P value < 0.05 was considered statistically significant ( 24 , 25 ).…”

Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis

“…They inhibit the activity of other T cells, especially CD8+ cytotoxic T cells, limit the immune response ( 39 ), reduce endothelial injury, and then impede PH-mediated vascular remodeling ( 40 , 41 ) by upregulating COX-2, PTGIS, HO-1, and PD-L1 in the media layer of the pulmonary arteriole ( 40 ). A previous study identified Treg-associated genes in the progression of PH, and the gene signature based on these genes was revealed to be a novel indicator to distinguish PH from controls ( 42 ). The imbalanced Th1/Th2 immune response has been considered central to the pathogenesis of PF ( 43 ); Treg impairment is also dedicated to the development of PF ( 44 ).…”

“…previous study identified Treg-associated genes in the progression of PH, and the gene based on these genes was revealed to be a novel indicator to distinguish PH from controls (42). The imbalanced Th1/Th2 immune response has been considered central to the pathogenesis of PF ( 43 +CD25hiFoxp3+ Tregs has been shown in bleomycin-induced PF and other types of fibrosis animals (31), so the potential role of Tregs in PF remains uncertain and can be controversial.…”

Regulatory T cells and cardiovascular diseases

“…[76] The progression of PAH can be partly attributed to the reduced number and impaired function of Tregs. [77] In a Treg-deficient PAH model, females experienced more severe PAH than males, indicating that females rely more on Treg function to ameliorate pulmonary vascular damage in PAH. [78] Impaired Treg response can exacerbate inflammationmediated endothelial injury, leading to PAH.…”

“…By analyzing data from 62 patients with PAH, researchers found that Treg dysfunction occurs in all forms of PAH [76] . The progression of PAH can be partly attributed to the reduced number and impaired function of Tregs [77] . In a Treg-deficient PAH model, females experienced more severe PAH than males, indicating that females rely more on Treg function to ameliorate pulmonary vascular damage in PAH [78] …”