Journal article
PGI2 signaling metabolically reprograms CD4 Th2 cells and represses allergic airway inflammation
The Journal of immunology (1950), Vol.214(9), pp.2270-2280
09/01/2025
DOI: 10.1093/jimmun/vkaf130
PMCID: PMC12481032
PMID: 40587812
Abstract
Prostaglandin I2 (PGI2) is a lipid mediator known to inhibit T helper 2 (Th2) immune responses and allergic inflammation, but its role in regulating Th2 cell metabolism remains underexplored. Using the Seahorse assay, we evaluated the effects of PGI2 signaling on Th2 cell glycolysis and mitochondrial respiration. Our results show that cicaprost, a stable PGI2 analog, significantly reduced basal, maximal, and spare glycolytic capacities in wild-type Th2 cells, while these effects are absent in Th2 cells lacking the PGI2 IP receptor (IP knockout [KO]). Cicaprost also impaired mitochondrial respiration and adenosine triphosphate production in wild-type Th2 cells, but not in IP KO cells, indicating that PGI2 signaling is essential for these metabolic changes. Further analysis revealed that cicaprost decreased glucose transporter 1 expression and glucose uptake and inhibited mitochondrial mass and membrane potential, suggesting that PGI2 signaling inhibits Th2 cell metabolism by reducing glucose availability and mitochondrial respiratory functions. Metabolomic profiling of cicaprost-treated Th2 cells showed dose-dependent changes, with 126 downregulated and 233 upregulated metabolites showing over 2-fold significant changes compared with vehicle-treated cells. Pathway analysis of these altered metabolites suggests a shift from catabolism to anabolism in cicaprost-treated Th2 cells. In vivo, CD4-specific conditional IP KO mice (CD4Cre+IPflox) exhibited exacerbated lung inflammation following exposure to Alternaria alternata extract, marked by increased IL-5 and IL-13 production, enhanced eosinophilia, and elevated mucus production. These findings establish a mechanistic link between PGI2-mediated immunoregulation and metabolic reprogramming, reinforcing its role as a key modulator of allergic inflammation.
Details
- Title: Subtitle
- PGI2 signaling metabolically reprograms CD4 Th2 cells and represses allergic airway inflammation
- Creators
- Weisong Zhou - Vanderbilt UniversityJian Zhang - Vanderbilt UniversityNowrin U Chowdhury - Children's Hospital of PhiladelphiaAllison E Norlander - Indiana University School of MedicineShinji Toki - Vanderbilt UniversityMasako Abney - Vanderbilt UniversityMark Rusznak - Vanderbilt UniversityKatherine N Gibson-Corley - Vanderbilt UniversityDaniel P Cook - University of IowaDawn C Newcomb - Vanderbilt UniversityRay Stokes Peebles Jr - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.214(9), pp.2270-2280
- DOI
- 10.1093/jimmun/vkaf130
- PMID
- 40587812
- PMCID
- PMC12481032
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- Oxford University Press
- Grant note
- R01 AI124456 / NIH HHS R01AI111820 / NIH HHS R01 AI145265 / NIH HHS R21 AI145397 / NIH HHS U19 AI095227 / NIH HHS
- Language
- English
- Electronic publication date
- 06/30/2025
- Date published
- 09/01/2025
- Academic Unit
- The University of Iowa Institute for Vision Research; Internal Medicine
- Record Identifier
- 9984843745402771
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