Journal article
PGI2 restricts trained ILC2 responses in allergic inflammation
The Journal of immunology (1950), Vol.214(7), pp.1582-1591
07/01/2025
DOI: 10.1093/jimmun/vkaf088
PMCID: PMC12311380
PMID: 40334085
Abstract
Pulmonary type 2 innate lymphoid cells (ILC2s) exhibit immune memory, termed "trained immunity," which enhances their activation following exposure to an independent protease-containing allergen. The role of prostaglandin I2 (PGI2), a cyclooxygenase (COX) pathway metabolite, in modulating these trained ILC2 responses remains unclear. PGI2 acts through its G protein-coupled receptor IP. We hypothesized that IP signaling inhibits ILC2 training. To test this hypothesis, we used a mouse ILC2 training model in which we challenged wild-type (WT) and IP knockout (KO) mice with Alternaria alternata extract (Alt) to induce ILC2 activation and training. After a 33-d resting period, ILC2 responses subsided to a homeostatic level. Mice were then intranasally challenged with papain to evaluate responses to an unrelated allergen. IP KO mice displayed significantly heightened ILC2 interleukin (IL)-13 expression and with concomitant increased eosinophilia in the lungs post-papain challenge compared with WT control mice. Notably, neither WT nor IP KO mice challenged with papain only, devoid of ILC2 training, exhibited lung type 2 responses. The augmented type 2 inflammation observed in IP KO mice following both Alt and papain challenges correlated with increased numbers and percentages of IL-13-producing ILC2s and greater mean fluorescence intensity of IL-13 compared with WT mice. Furthermore, RNA sequencing of sorted ILC2s from WT and IP KO mice following Alt-papain challenges revealed heightened activation of immune response pathways and mitochondrial respiratory pathways in IP-deficient ILC2s. These findings reveal an inhibitory role of PGI2 signaling in trained ILC2 responses, emphasizing its pivotal contribution to innate immune responses and allergic inflammation.
Details
- Title: Subtitle
- PGI2 restricts trained ILC2 responses in allergic inflammation
- Creators
- Weisong Zhou - Vanderbilt University School of MedicineJian Zhang - Vanderbilt University School of MedicineAllison E Norlander - Indiana University School of MedicineDaniel P Cook - University of IowaShinji Toki - Vanderbilt University School of MedicineMasako Abney - Vanderbilt University School of MedicineMark Rusznak - Vanderbilt University School of MedicineChristopher Thomas - Vanderbilt University School of MedicineChristian Warren - VA Tennessee Valley Healthcare SystemBradley W Richmond - Vanderbilt University School of MedicineKatherine Gibson-Corley - Vanderbilt University School of MedicineGinger L Milne - Vanderbilt University School of MedicineDawn C Newcomb - Vanderbilt University School of MedicineR Stokes Peebles Jr - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.214(7), pp.1582-1591
- DOI
- 10.1093/jimmun/vkaf088
- PMID
- 40334085
- PMCID
- PMC12311380
- NLM abbreviation
- J Immunol
- ISSN
- 1550-6606
- eISSN
- 1550-6606
- Publisher
- Oxford Academic
- Grant note
- R01 AI124456 / NIH HHS 101BX004299 / U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service
- Language
- English
- Electronic publication date
- 05/07/2025
- Date published
- 07/01/2025
- Academic Unit
- The University of Iowa Institute for Vision Research; Internal Medicine
- Record Identifier
- 9984820565502771
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