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Metabolic regulation by prostaglandin E 2 impairs lung group 2 innate lymphoid cell responses
  • +11
  • Calum T. Robb,
  • You Zhou,
  • Jennifer M. Felton,
  • Birong Zhang,
  • Marie Goepp,
  • Privjyot Jheeta,
  • Danielle J. Smyth,
  • Richard M. Breyer,
  • Shuh Narumiya,
  • Henry J. McSorley,
  • Rick Maizels,
  • Jürgen Schwarze,
  • Adriano G. Rossi,
  • Chengcan Yao
Calum T. Robb
The University of Edinburgh Centre for Inflammation Research

Corresponding Author:[email protected]

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You Zhou
Cardiff University Cardiff Division of Infection and Immunity
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Jennifer M. Felton
The University of Edinburgh Centre for Inflammation Research
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Birong Zhang
Cardiff University Cardiff Division of Infection and Immunity
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Marie Goepp
The University of Edinburgh Centre for Inflammation Research
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Privjyot Jheeta
The University of Edinburgh Centre for Inflammation Research
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Danielle J. Smyth
University of Dundee Division of Cell Signalling and Immunology
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Richard M. Breyer
Vanderbilt University Medical Center
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Shuh Narumiya
Kyoto Daigaku Daigakuin Igaku Kenkyuka Medical Innovation Center
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Henry J. McSorley
University of Dundee Division of Cell Signalling and Immunology
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Rick Maizels
University of Glasgow Wellcome Centre for Molecular Parasitology
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Jürgen Schwarze
The University of Edinburgh Centre for Inflammation Research
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Adriano G. Rossi
The University of Edinburgh Centre for Inflammation Research
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Chengcan Yao
The University of Edinburgh Centre for Inflammation Research
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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- and Alternaria alternata (A.A.)-induced lung allergy models. 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 lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 but not EP2 markedly restricts IL-33- and Alternaria alternata-induced lung ILC2 responses and eosinophilic inflammation. 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 lacking endogenous PG synthesis but not in PG-competent mice. Conclusion: We have defined a mechanism for optimal suppression of 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 ILC2-initiated lung inflammation in asthma and NERD.
27 Dec 2021Submitted to Allergy
27 Dec 2021Submission Checks Completed
27 Dec 2021Assigned to Editor
28 Dec 2021Reviewer(s) Assigned
11 Jan 2022Review(s) Completed, Editorial Evaluation Pending
11 Jan 2022Editorial Decision: Revise Minor
25 Jul 20221st Revision Received
25 Jul 2022Submission Checks Completed
25 Jul 2022Assigned to Editor
30 Jul 2022Reviewer(s) Assigned
11 Aug 2022Review(s) Completed, Editorial Evaluation Pending
13 Aug 2022Editorial Decision: Revise Minor
16 Sep 20222nd Revision Received
16 Sep 2022Submission Checks Completed
16 Sep 2022Assigned to Editor
18 Sep 2022Review(s) Completed, Editorial Evaluation Pending
18 Sep 2022Editorial Decision: Accept