Abstract
Type 2 innate lymphoid cells (ILC2) are a population of lineage-negative cells in the lung, gastrointestinal tract, and skin which have emerged as a significant component of type 2 allergic inflammation. The regulation of cyclooxygenase-2 (COX-2) metabolites is critical to the pathophysiology of many inflammatory disorders, including allergic asthma. While COX-2 regulates Th9 and Th17 cell differentiation and function during allergic lung inflammation, it remains unknown whether COX-2 also regulates ILC2 cell differentiation and function under similar conditions. To address this question, we examined lung ILC2 cells from COX-2+/+ and COX-2-/- mice after ovalbumin (OVA)- or Alternaria-induced allergic lung inflammation. ILC2 cells were significantly increased in COX-2-/- lungs compared with COX-2+/+ lungs after OVA exposure in vivo. The increase in ILC2 cells was accompanied by an increase in expression of the cytokines IL-5 and IL-13, and the transcription factor GATA3. Both genetic disruption and selective inhibition of COX-2 significantly increased ILC2 cell differentiation from isolated common lymphoid progenitor cells (CLP) in vitro. Furthermore, COX-2-derived PGE2 acting via EP2 receptors significantly reduced IL-33 and TSLP expression, and attenuated ILC2 cell differentiation in vitro and in vivo. Thus, during allergic lung inflammation, COX-2-derived PGE2 signals through the EP2 receptor to negatively regulate lung ILC2 cell differentiation and function.
Authors
Hong Li, Matthew L. Edin, Daniel Menendez, J. Alyce Bradbury, Joan P. Graves, Artiom Gruzdev, Gregory S. Whitehead, Maria I Sifre, Laura M. DeGraff, Darryl C. Zeldin
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