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

TY - JOUR

T1 - Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses

AU - Robb, Calum T.

AU - Zhou, You

AU - Felton, Jennifer M.

AU - Zhang, Birong

AU - Goepp, Marie

AU - Jheeta, Privjyot

AU - Smyth, Danielle J.

AU - Duffin, Rodger

AU - Vermeren, Sonja

AU - Breyer, Richard M.

AU - Narumiya, Shuh

AU - McSorley, Henry J.

AU - Maizels, Rick M.

AU - Schwarze, Jürgen K. J.

AU - Rossi, Adriano G.

AU - Yao, Chengcan

N1 - Funding Information: We thank E. Dzierzak for providing Vav-Cre mice; P.J. Brophy and D. Mahad for CD90.2(Thy1.2)-iCre mice; and C. Ffrench-Constant for Rag2–/– mice. We also thank P. Dos Santos Coelho for help with Seahorse assays; staff at the University of Edinburgh QMRI and SCRM flow cytometry facilities for cell sorting and analysis; staff at the University of Edinburgh LFR and SCRM animal facilities for technical support; and C. Elder and M. McIlorum for technical assistance. This work is supported in part by UKRI Medical Research Council (MR/R008167/1 to C.Y.), Cancer Research UK (C63480/A25246 to C.Y.). M.G. received a CMVM Research Adaptation Funding support. Copyright: © 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

PY - 2023/3/3

Y1 - 2023/3/3

N2 - 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.

AB - 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.

KW - NSAID-exacerbated respiratory disease (NERD)

KW - Group 2 innate lymphoid cell (ILC2)

KW - lung allergy

KW - prostaglandin E2 (PGE2)

KW - EP2

KW - EP4

KW - cellular metabolism

KW - group 2 innate lymphoid cell (ILC2)

KW - NSAID-exacerbated respiratory disease

KW - prostaglandin E

UR - https://www.scopus.com/pages/publications/85139823478

U2 - 10.1111/all.15541

DO - 10.1111/all.15541

M3 - Article

C2 - 36181709

SN - 0105-4538

VL - 78

SP - 714

EP - 730

JO - Allergy

JF - Allergy

IS - 3

ER -