COX inhibition enhances allergen-induced IL-33 release and ILC2 responses in mouse lungs

Abstract

Abstract The cyclooxygenase (COX) metabolic pathway has regulatory functions in immune responses and inflammation. However, the effect of the COX pathway on innate airway inflammation induced by protease-containing allergens such as Alternaria alternata is not fully defined. Here we show that COX inhibition augmented innate lung type 2 responses after repeated airway exposures to Alternaria extract in mice. We treated wild type BALB/c and IL-33 KO mice with either the COX inhibitor indomethacin or vehicle in drinking water and challenged mice intranasally with Alternaria extract for 4 consecutive days to induce innate lung inflammation. We found that indomethacin significantly increased the numbers of group 2 innate lymphoid cells (ILC2) and IL-5+IL-13+ ILC2 in the lung. Indomethacin also increased type 2 cytokine (IL-5 and IL-13) responses, the percentages of eosinophils, and mucus production in the lung. IL-33 is required for Alt-induced lung ILC2 responses, and indomethacin did not change IL-5 and IL-13 expression in IL-33 KO mice. Consistently, indomethacin increased the release of IL-33 in bronchoalveolar lavage fluid after Alternaria challenge, suggesting that more IL-33 was available for ILC2 activation. Indomethacin also increased reactive oxygen species (ROS) production in the lung, providing a possible mechanism for the increased IL-33 release. Although contrasting effects of PGD2 and PGE2/PGI2 on ILC2 responses have been previously reported, the overall effect of COX pathway on ILC2 function is inhibitory in Alternaria extract-induced airway innate type 2 responses.