Cycloxygenase-2 negatively regulates innate lymphoid cell type 2 differentiation and function during allergic lung inflammation

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

doi:10.1172/jci.insight.189205

Cycloxygenase-2 negatively regulates innate lymphoid cell type 2 differentiation and function during allergic lung inflammation

Hong Li,¹ Matthew L. Edin,¹ Daniel Menendez,¹ J. Alyce Bradbury,¹ Joan P. Graves,¹ Artiom Gruzdev,¹ Gregory S. Whitehead,¹ Maria I Sifre,¹ Laura M. DeGraff,¹ and Darryl C. Zeldin¹

Published September 22, 2026 - More info

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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.

Cycloxygenase-2 negatively regulates innate lymphoid cell type 2 differentiation and function during allergic lung inflammation

Hong Li,¹ Matthew L. Edin,¹ Daniel Menendez,¹ J. Alyce Bradbury,¹ Joan P. Graves,¹ Artiom Gruzdev,¹ Gregory S. Whitehead,¹ Maria I Sifre,¹ Laura M. DeGraff,¹ and Darryl C. Zeldin¹

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Cycloxygenase-2 negatively regulates innate lymphoid cell type 2 differentiation and function during allergic lung inflammation

Hong Li,1 Matthew L. Edin,1 Daniel Menendez,1 J. Alyce Bradbury,1 Joan P. Graves,1 Artiom Gruzdev,1 Gregory S. Whitehead,1 Maria I Sifre,1 Laura M. DeGraff,1 and Darryl C. Zeldin1

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Hong Li,¹ Matthew L. Edin,¹ Daniel Menendez,¹ J. Alyce Bradbury,¹ Joan P. Graves,¹ Artiom Gruzdev,¹ Gregory S. Whitehead,¹ Maria I Sifre,¹ Laura M. DeGraff,¹ and Darryl C. Zeldin¹