Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

Rationale: Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytolcines central to the asthma phenotype; however, the effect of prostaglandin (PG) I-2 on ILC2 function is unknown. Objectives: To determine the effect of PGI(2) on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI(2) and the PGI(2) analog cicaprost on lung ILC2s in vivo. Methods: Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI(2) receptor-deficient (IP-/-) mice were cultured with IL-33 and treated with the PGI(2) analog cicaprost. WT and IP-/- mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI(2) analog cicaprost. Measurement and Main Results: We demonstrate that PGI(2) inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI(2) receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI(2) signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI(2) analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI(2) analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33. Conclusions: These results suggest that PGI(2) may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.