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\begin{document}

\title{Metabolic regulation by prostaglandin E 2 impairs lung group 2 innate
lymphoid cell responses}



\author[1]{Calum T. Robb}%
\author[2]{You Zhou}%
\author[1]{Jennifer M. Felton}%
\author[2]{Birong Zhang}%
\author[1]{Marie Goepp}%
\author[1]{Privjyot Jheeta}%
\author[3]{Danielle J. Smyth}%
\author[4]{Richard M. Breyer}%
\author[5]{Shuh Narumiya}%
\author[3]{Henry J. McSorley}%
\author[6]{Rick Maizels}%
\author[1]{Jürgen Schwarze}%
\author[1]{Adriano G. Rossi}%
\author[1]{Chengcan Yao}%
\affil[1]{The University of Edinburgh Centre for Inflammation Research}%
\affil[2]{Cardiff University Cardiff Division of Infection and Immunity}%
\affil[3]{University of Dundee Division of Cell Signalling and Immunology}%
\affil[4]{Vanderbilt University Medical Center}%
\affil[5]{Kyoto Daigaku Daigakuin Igaku Kenkyuka Medical Innovation Center}%
\affil[6]{University of Glasgow Wellcome Centre for Molecular Parasitology}%


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  \date{May 17, 2024}


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\begin{abstract}
\textbf{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
\textsubscript{2} (PGE \textsubscript{2}). However, the respective roles
for the PGE \textsubscript{2} receptors EP2 and EP4 (both share same
downstream signaling) in the regulation of lung ILC2 responses has yet
been deciphered. \textbf{Methods:} The roles of PGE \textsubscript{2}
receptors EP2 and EP4 on ILC2-mediated lung inflammation were
investigated using genetically modified mouse lines and pharmacological
approaches in IL-33- and \emph{Alternaria alternata} (A.A.)-induced lung
allergy models. The effects of PGE \textsubscript{2} receptors and
downstream signals on ILC2 metabolic activation and effector function
were examined using \emph{in vitro} cell cultures. \textbf{Results:}
Deficiency of EP2 rather than EP4 augments IL-33-induced lung ILC2
responses and eosinophilic inflammation \emph{in vivo}. In contrast,
exogenous agonism of EP4 but not EP2 markedly restricts IL-33- and
\emph{Alternaria alternata}-induced lung ILC2 responses and eosinophilic
inflammation. Mechanistically, PGE \textsubscript{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. \textbf{Conclusion:} We have defined a mechanism for
optimal suppression of lung ILC2 responses by endogenous PGE
\textsubscript{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 \textsubscript{2}-EP4-cAMP
and energy metabolic pathways may provide novel opportunities for
treating ILC2-initiated lung inflammation in asthma and NERD.%
\end{abstract}%



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\textbf{Hosted file}

\verb`Robb et al_Manuscript.docx`  available at \url{https://authorea.com/users/452901/articles/550872-metabolic-regulation-by-prostaglandin-e-2-impairs-lung-group-2-innate-lymphoid-cell-responses}

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