AUTHOR=Zhou Yu , Wang Wei , Zhao Conghui , Wang Yan , Wu Haoming , Sun Xiuyuan , Guan Youfei , Zhang Yu 

TITLE=Prostaglandin E2 Inhibits Group 2 Innate Lymphoid Cell Activation and Allergic Airway Inflammation Through E-Prostanoid 4-Cyclic Adenosine Monophosphate Signaling

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00501

DOI=10.3389/fimmu.2018.00501

ISSN=1664-3224

ABSTRACT=<p>Evidence is accumulating that group 2 innate lymphoid cells (ILC2) play an important role in allergic airway inflammation by producing a large amount of type 2 cytokines. But it remains poorly understood how its activities are properly controlled <italic>in vivo</italic>. Here, we demonstrated that prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) had a profound inhibitory effect on IL-33-induced ILC2 expansion and IL-5 and IL-13 production <italic>in vitro</italic>. This effect was mimicked by PGE<sub>1</sub>-alcohol but attenuated by ONO-AE3-208, indicating a selective action through the E-prostanoid 4 (EP4) receptor. In the IL-33-induced asthma model, coadministration of PGE<sub>2</sub> or PGE<sub>1</sub>-alcohol resulted in diminished IL-5 and IL-13 production, reduced eosinophilia and alleviated lung pathology. In contrast, EP4-deficient mice displayed an exacerbated inflammatory response in another ILC2-mediated asthma model induced by <italic>Alternaria</italic> extract. Mechanistic studies demonstrated that the PGE<sub>2</sub>-mediated inhibition of ILC2 was dependent on cyclic adenosine monophosphate (cAMP) production. Further downstream, PGE<sub>2</sub>-EP4-cAMP signaling led to suppression of GATA3 and ST2 expression, which is known to be critical for ILC2 activation. These findings reveal a novel function of PGE<sub>2</sub> as a negative regulator of ILC2 activation and highlight an endogenous counter-regulatory mechanism for the control of innate allergic inflammatory responses.</p>