title: IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk.
abstract: BACKGROUND
  Mast cell localization within the airway smooth muscle (ASM)-bundle plays an important role in the development of airway hyper-responsiveness (AHR). Genomewide association studies implicate the 'alarmin' IL-33 in asthma, but its role in mast cell-ASM interactions is unknown.
  
  
  OBJECTIVE
  We examined the expression and functional role of IL-33 in bronchial biopsies of patients with and without asthma, ex vivo ASM, mast cells, cocultured cells and in a mouse model system.
  
  
  METHODS
  IL-33 protein expression was assessed in human bronchial tissue from 9 healthy controls, and 18 mild-to-moderate and 12 severe asthmatic patients by immunohistochemistry. IL-33 and ST2 mRNA and protein expression in human-derived ASM, epithelial and mast cells were assessed by qPCR, immunofluorescence and/or flow cytometry and ELISA. Functional assays were used to assess calcium signalling, wound repair, proliferation, apoptosis and contraction. AHR and inflammation were assessed in a mouse model.
  
  
  RESULTS
  Bronchial epithelium and ASM expressed IL-33 with the latter in asthma correlating with AHR. ASM and mast cells expressed intracellular IL-33 and ST2. IL-33 stimulated mast cell IL-13 and histamine secretion independent of FcεR1 cross-linking and directly promoted ASM wound repair. Coculture of mast cells with ASM activated by IL-33 increased agonist-induced ASM contraction, and in vivo IL-33 induced AHR in a mouse cytokine installation model; both effects were IL-13 dependent.
  
  
  CONCLUSIONS
  IL-33 directly promotes mast cell activation and ASM wound repair but indirectly promotes ASM contraction via upregulation of mast cell-derived IL-13. This suggests that IL-33 may present an important target to modulate mast cell-ASM crosstalk in asthma.
authors: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors: D
authors: D
authors: Kaur
authors: E
authors: E
authors: Gomez
authors: C
authors: C
authors: Doe
authors: R
authors: R
authors: Berair
authors: L
authors: L
authors: Woodman
authors: R
authors: R
authors: Saunders
authors: F
authors: F
authors: Hollins
authors: F R
authors: FR
authors: Rose
authors: Y
authors: Y
authors: Amrani
authors: R
authors: R
authors: May
authors: J
authors: J
authors: Kearley
authors: A
authors: A
authors: Humbles
authors: E S
authors: ES
authors: Cohen
authors: C E
authors: CE
authors: Brightling
mesh_terms: D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000276:immunology*; D000067596:Interleukin-33 / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009130:Muscle, Smooth / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000276:immunology*
chemical_list: D018793:Interleukin-13; D000067596:Interleukin-33
keywords: ASM; IL-33; mast cells