title: IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo.
abstract: BACKGROUND
  Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation.
  
  
  OBJECTIVE
  To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway.
  
  
  METHODS
  We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade.
  
  
  RESULTS
  IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33.
  
  
  CONCLUSIONS
  IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33-responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.
authors.affiliation: 1 Airway Disease Infection Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Jackson
authors.forename: Heidi
authors.initials: H
authors.lastname: Makrinioti
authors.forename: Batika M J
authors.initials: BM
authors.lastname: Rana
authors.forename: Betty W H
authors.initials: BW
authors.lastname: Shamji
authors.forename: Maria-Belen
authors.initials: MB
authors.lastname: Trujillo-Torralbo
authors.forename: Joseph
authors.initials: J
authors.lastname: Footitt
authors.lastname: Jerico Del-Rosario
authors.forename: Aurica G
authors.initials: AG
authors.lastname: Telcian
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nikonova
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Julia
authors.initials: J
authors.lastname: Aniscenko
authors.forename: Leila
authors.initials: L
authors.lastname: Gogsadze
authors.forename: Eteri
authors.initials: E
authors.lastname: Bakhsoliani
authors.forename: Stephanie
authors.initials: S
authors.lastname: Traub
authors.forename: Jaideep
authors.initials: J
authors.lastname: Dhariwal
authors.forename: James
authors.initials: J
authors.lastname: Porter
authors.forename: Duncan
authors.initials: D
authors.lastname: Hunt
authors.forename: Toby
authors.initials: T
authors.lastname: Hunt
authors.forename: Trevor
authors.initials: T
authors.lastname: Hunt
authors.forename: Luminita A
authors.initials: LA
authors.lastname: Stanciu
authors.forename: Musa
authors.initials: M
authors.lastname: Khaitov
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
authors.forename: Onn Min
authors.initials: OM
authors.lastname: Kon
authors.forename: Patrick
authors.initials: P
authors.lastname: Mallia
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Papadopoulos
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
authors.forename: John
authors.initials: J
authors.lastname: Westwick
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: David J
authors.initials: DJ
authors.lastname: Cousins
authors.forename: Ross P
authors.initials: RP
authors.lastname: Walton
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
mesh_terms: D000328:Adult; D001249:Asthma / Q000209:etiology* / Q000503:physiopathology / Q000821:virology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000503:physiopathology; D018793:Interleukin-13 / Q000502:physiology; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000502:physiology; D015848:Interleukin-5 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000502:physiology; D008297:Male; D010850:Picornaviridae Infections / Q000150:complications* / Q000503:physiopathology; D012229:Rhinovirus; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology; D019562:Viral Load
chemical_list: C506536:IL33 protein, human; D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D015847:Interleukin-4
keywords: ILC2; Th2; infection; virus