CYCLOXYGENASE (COX-2) NEGATIVELY REGULATES LUNG INNATE LYMPHOID TYPE 2 (ILC2) CELL DIFFERENTIATION DURING ALLERGIC LUNG INFLAMMATION

Authors

• H Li
• JA Bradbury
• ML Edin
• JP Graves
• A Gruzdev
• LM DeGraff
• DC Zeldin

Abstract

Type II innate lymphoid cells (ILC2s) are a population of lineage-negative cells that produce Th2 cytokines, including IL-5, IL-9 and IL-13. Epithelial cytokines IL-25, IL-33, and TSLP potently activate ILC2s. Our previous work showed that COX-2-derived prostaglandins reduce Th9 differentiation during allergic lung inflammation. To determine whether COX-2 also regulates ILC2 differentiation, lung ILC2s from COX-2-/- and COX-2+/+ mice were examined after ovalbumin-induced allergic lung inflammation. ILC2s were significantly increased in COX-2-/- compared to COX-2+/+ lungs after OVA sensitization/exposure. To determine the mechanism of COX-2 regulation of ILC2 differentiation, we isolated common lymphoid progenitor cells (CLPs) from COX-2+/+ and COX-2-/- bone marrow and differentiated them to ILC2s in vitro with IL-7, SCF and IL-33. COX-2-/- CLPs exhibited significantly increased ILC2 differentiation compared with COX-2+/+ CLPs. The COX-2 selective inhibitor NS-398 also enhanced ILC2 differentiation from CLPs. PGE2 significantly attenuated ILC2 differentiation from both COX-2+/+ and COX-2-/- CLPs. ILC2s express EP2 and EP3 receptors. EP2 antagonists increased ILC2 differentiation in vitro and in vivo. The EP2 agonist CAY10399 decreased ILC2 differentiation during allergic lung inflammation in vivo. Immunofluorescent staining and mRNA analysis revealed that allergic COX-2-/- lungs had increased IL-33 and TSLP expression compared with COX-2+/+ lungs. PGE2 significantly suppressed IL-33 and TSLP expression in purified airway epithelial cells stimulated with LPS in vitro. In contrast, COX-2+/+ and COX-2-/- lungs have comparable numbers of ILC2s when IL-33 was used to induce allergic lung inflammation. Together, these data indicate that during allergic lung inflammation, COX-2-derived PGE2 signals through the EP2 receptor to negatively regulate lung ILC2 differentiation in vivo and in vitro. COX-2-derived PGE2 also suppresses epithelial-derived IL-33 and TSLP to reduce ILC2 differentiation in vivo.

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