Prostaglandin I₂Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

Abstract

Rationale: Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines 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 2/2 ) mice were cultured with IL-33 and treated with the PGI 2 analog cicaprost. WT and IP 2/2 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.

Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

“…Lipoxin A 4 , derived from arachidonic acid, also inhibits IL-13 production from human ILC2s (46). A recent publication reported that an analogue of prostacyclin inhibited IL-33-induced IL-5 and IL-13 production from both mouse and human ILC2s (47). Consistently, our study also indicates prostacyclin as an inhibitory regulator because iloprost directly suppressed ILC2 proliferation.…”

“…Consistently, our study also indicates prostacyclin as an inhibitory regulator because iloprost directly suppressed ILC2 proliferation. As demonstrated in the report (47), IP-mediated signaling could be a new target for regulating ILC2s in the treatment of allergic diseases.…”

Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation

“…IL-5 production is imperative for infiltration of eosinophils into the airway, a key pathologic feature of allergy, and IL-13 is important for increased airway hyperresponsiveness and mucus production (Halim et al, 2012a). ILC2 secrete more IL-5 and IL-13 compared to CD4+ T cells and are also important for establishing a memory Th2 allergic response in the lung and skin, underscoring the substantial pathophysiologic potential of ILC2 (Halim et al, 2014; Klein Wolterink et al, 2012; Zhou et al, 2016). …”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…Similar detrimental roles of IL-13-producing ILC2s were demonstrated in a mouse model of C. neoformans -induced airway inflammation [126] and in patients with Aspergillus -mediated chronic sinusitis [127]. Interestingly, prostaglandin I2 can reduce the number of Th2-expressing ILC2 in the lung, such as IL-13 and IL-5, and could potentially be exploited as a therapeutic strategy in this context [128]. …”