title: Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses.
abstract: BACKGROUND
  Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines central to the asthma phenotype; however, the effect of prostaglandin (PG) I2 on ILC2 function is unknown.
  
  
  OBJECTIVE
  To determine the effect of PGI2 on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI2 and the PGI2 analog cicaprost on lung ILC2s in vivo.
  
  
  METHODS
  Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI2 receptor-deficient (IP(-/-)) mice were cultured with IL-33 and treated with the PGI2 analog cicaprost. WT and IP(-/-) mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI2 analog cicaprost.
  
  
  RESULTS
  We demonstrate that PGI2 inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI2 receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI2 signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI2 analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI2 analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33.
  
  
  CONCLUSIONS
  These results suggest that PGI2 may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Weisong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Shinji
authors.initials: S
authors.lastname: Toki
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewksa
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Jacqueline Y
authors.initials: JY
authors.lastname: Cephus
authors.affiliation: 2 Division of Infectious Diseases, Department of Pediatrics, and.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Dulek
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Bloodworth
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Stier
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Vasiliy
authors.initials: V
authors.lastname: Polosuhkin
authors.affiliation: 3 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Rama D
authors.initials: RD
authors.lastname: Gangula
authors.affiliation: 3 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.affiliation: 4 Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.affiliation: 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: R Stokes
authors.identifier: http://orcid.org/0000-0002-1429-7875
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000528:Alternaria / Q000276:immunology; D000818:Animals; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000502:physiology; D000067596:Interleukin-33 / Q000494:pharmacology; D015848:Interleukin-5 / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D011464:Epoprostenol; C043867:cicaprost
keywords: ILC2; PGI2; allergy; asthma