The Prostaglandin D 2 Receptor CRTH2 Promotes IL-33-Induced ILC2 Accumulation in the Lung

J Immunol. 2020 Feb 15;204(4):1001-1011. doi: 10.4049/jimmunol.1900745. Epub 2020 Jan 3.

Abstract

Group 2 innate lymphoid cells (ILC2s) are rare innate immune cells that accumulate in tissues during allergy and helminth infection, performing critical effector functions that drive type 2 inflammation. ILC2s express ST2, the receptor for the cytokine IL-33, and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a receptor for the bioactive lipid prostaglandin D2 (PGD2). The IL-33-ST2 and the PGD2-CRTH2 pathways have both been implicated in promoting ILC2 accumulation during type 2 inflammation. However, whether these two pathways coordinate to regulate ILC2 population size in the tissue in vivo remains undefined. In this study, we show that ILC2 accumulation in the murine lung in response to systemic IL-33 treatment was partially dependent on CRTH2. This effect was not a result of reduced ILC2 proliferation, increased apoptosis or cell death, or differences in expression of the ST2 receptor in the absence of CRTH2. Rather, data from adoptive transfer studies suggested that defective accumulation of CRTH2-deficient ILC2s in response to IL-33 was due to altered ILC2 migration patterns. Whereas donor wild-type ILC2s preferentially accumulated in the lungs compared with CRTH2-deficient ILC2s following transfer into IL-33-treated recipients, wild-type and CRTH2-deficient ILC2s accumulated equally in the recipient mediastinal lymph node. These data suggest that CRTH2-dependent effects lie downstream of IL-33, directly affecting the migration of ILC2s into inflamed lung tissues. A better understanding of the complex interactions between the IL-33 and PGD2-CRTH2 pathways that regulate ILC2 population size will be useful in understanding how these pathways could be targeted to treat diseases associated with type 2 inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Movement / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Humans
  • Hypersensitivity / immunology*
  • Hypersensitivity / pathology
  • Immunity, Innate
  • Interleukin-33 / administration & dosage
  • Interleukin-33 / immunology*
  • Lung / cytology
  • Lung / immunology
  • Lung / pathology
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Mice
  • Mice, Knockout
  • Nippostrongylus / immunology
  • Primary Cell Culture
  • Prostaglandin D2 / immunology
  • Prostaglandin D2 / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism*
  • Receptors, Prostaglandin / genetics
  • Receptors, Prostaglandin / immunology
  • Receptors, Prostaglandin / metabolism*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / immunology
  • Strongylida Infections / immunology*
  • Strongylida Infections / parasitology
  • Strongylida Infections / pathology

Substances

  • Il33 protein, mouse
  • Interleukin-33
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • Recombinant Proteins
  • Prostaglandin D2
  • prostaglandin D2 receptor