Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses

Calum T Robb, You Zhou, Jennifer M Felton, Birong Zhang, Marie Goepp, Privjyot Jheeta, Danielle J Smyth, Rodger Duffin, Sonja Vermeren, Richard M Breyer, Shuh Narumiya, Henry J McSorley, Rick M Maizels, Jürgen K J Schwarze, Adriano G Rossi, Chengcan Yao

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E 2 (PGE 2 ). However, the respective roles for the PGE 2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered.

METHODS: The roles of PGE 2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE 2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures.

RESULTS: Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE 2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE 2 -EP2 signaling.

CONCLUSION: We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE 2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE 2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.

Original languageEnglish
JournalAllergy
Early online date1 Oct 2022
DOIs
Publication statusE-pub ahead of print - 1 Oct 2022

Keywords

  • NSAID-exacerbated respiratory disease
  • cellular metabolism
  • group 2 innate lymphoid cell (ILC2)
  • lung allergy
  • prostaglandin E

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