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• W4225418395 abstract "Hypoxic pulmonary hypertension (PH) can be caused by chronic obstructive lung diseases, acute lung injury, sleep apnea, and high altitude. Hallmarks for PH include recruitment of immune cells to the perivascular region of the lungs, thickening of the pulmonary arterial walls, elevated pulmonary vascular resistance and pressure, and right ventricular remodeling, ultimately causing right heart failure and death. We previously reported that chronic hypoxia (CH) leads to an upregulation of pro-inflammatory Th17 cells but does not alter T regulatory (Treg) cell numbers within the lung. This change in Th17-Treg ratio can upset the pro-inflammatory/anti-inflammatory balance required to maintain homeostasis leading to disease pathogenesis. We also demonstrated that these Th17 cells react to the cryptic self-antigen collagen V (col V), which is upregulated following CH. Nasally instilling mice with col V attenuated CH-induced PH, presumably by inducing mucosal tolerance to col V and restoring Treg-Th17 balance. Tregs can lose their suppressive phenotype and transition into Th17 cells (deemed exTreg Th17 cells) in certain autoimmune conditions. However, it is unknown whether CH triggers this mechanism. We hypothesized that CH disrupts the Th17-Treg cell balance due to the pathogenic conversion of Tregs into Th17 cells, contributing to PH development. Using a mouse model (Foxp3tm9(EGFP/cre/ERT2)Ayr /J x Ai14-tdTomato) that allows the study of lineage stability and genetic mapping of Tregs, together with single-cell RNA sequencing, we discovered that CH resulted in a gene expression profile consistent with exTregs or Tregs with less suppressive activity, such as downregulation of Il2ra and upregulation of Tnfrsf4 within CD4 memory T cell cluster (adjusted p-value 0.03). The single-cell sequencing data were processed with the conventional pipeline. Seurat (v4.0.5), R (v4.1.0), single R (v1.6.1) were used for downstream analysis and cell type prediction against the mouse Immunologic Genome Project. Differential gene expression was determined using the R package DESEq2, and significant genes were defined by adjusted p-value ≤ 0.05. Our future studies include using multicolor flow cytometry to characterize these changes further and determine if and how CH decreases Treg suppressive activity, contributing to the phenotypic switch to Th17 cells. In conclusion, our data suggest that CH alters Treg cell phenotype, which aids in the pathogenesis of PH." @default.
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• W4225418395 date "2022-05-01" @default.
• W4225418395 modified "2023-09-27" @default.
• W4225418395 title "Altered T Regulatory Cell Phenotype due to Chronic Hypoxia Exposure Contributes to the Pathogenesis of Pulmonary Hypertension" @default.
• W4225418395 doi "https://doi.org/10.1096/fasebj.2022.36.s1.r5115" @default.
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