Chronic hypoxia disrupts memory T regulatory cell phenotype which contributes to the pathogenesis of pulmonary hypertension

• Published in: Physiology (Bethesda, Md.) Vol. 38; no. S1
• Main Authors: Lantz, Benjamin, Moriwaki, Mika, Oyebamiji, Olufunmilola, Guo, Yan, Garcia, Selina, Gonzalez Bosc, Laura
• Format: Journal Article
• Language: English
• Published: 01-05-2023
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5795168

Abstract only
Pulmonary hypertension (PH) caused by chronic hypoxia (CH) is a multifaceted disease most often caused by sleep apnea, prolonged high-altitude exposure, or chronic obstructive pulmonary disease (COPD), with minimal treatment options, leading to right heart failure and death. One major contributor in the pathogenesis of PH that requires more characterization is the accompanying immune response.Our previous studies have demonstrated the importance of inflammation and self-immunity in CH-induced PH. We demonstrated pulmonary-perivascular localization of pro-inflammatory Th17 cells as well as an increase in total Th17 cells in the lung, while finding no overall changes in the number of anti-inflammatory T regulatory (Treg) cells present in the lung. Imbalance between Th17 and Treg cells has been shown to drive multiple inflammatory and metabolic diseases. One area of interest related to this balance has been the recent discovery and attempted characterization of exTregs, or cells that, at one point in time, were Tregs but lost their phenotype transitioning to pro-inflammatory Th17 cells, due to decreases in the expression of the transcription factor FoxP3. Therefore, we hypothesized that the increase in Th17 cells seen in CH is due to a decrease in Tregs and Treg suppressive capacity as well as a switching of Tregs to Th17 cells. Using a mouse model that allows the study of lineage stability and genetic mapping of Tregs, together with single-cell RNA sequencing (scRNA SEQ), we initially established that CH resulted in a gene expression profile consistent with exTregs or Tregs with less suppressive activity, such as downregulation of Il2ra gene and upregulation of Tnfrsf4 (adjusted p-value 0.03). To further establish a loss in Tregs as well as an increase in exTregs following CH exposure, we performed spectral flow cytometry of splenocytes on a Cytek Aurora to look for changes in protein expression and cell prevalence. Finally, we used a similar lineage mapping mouse model to look at Th17 cells. Following these experiments, we found supporting evidence of our scRNA SEQ data, finding a decrease in Tregs in both male and female mice following CH exposure, as well as an increase in exTregs in both groups exposed to CH. We also further supported this data finding Th17 cells tracked through our model to be increased following CH. These results support the importance of immune cell balance and inflammation in the pathogenesis of CH-induced PH.
R56 HL153065-01 NIH, AHA 18TPA34170037, AHA967925 & T32 HL07736 NIH
This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.