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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 in vivo. Here, we demonstrated that prostaglandin E₂ (PGE₂) had a profound inhibitory effect on IL-33-induced ILC2 expansion and IL-5 and IL-13 production in vitro. This effect was mimicked by PGE₁-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 PGE₂ or PGE₁-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 Alternaria extract. Mechanistic studies demonstrated that the PGE₂-mediated inhibition of ILC2 was dependent on cyclic adenosine monophosphate (cAMP) production. Further downstream, PGE₂-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 PGE₂ as a negative regulator of ILC2 activation and highlight an endogenous counter-regulatory mechanism for the control of innate allergic inflammatory responses.