title: Toll-like receptor-induced expression of epithelial cytokine receptors on haemopoietic progenitors is altered in allergic asthma.
abstract: BACKGROUND
  Haemopoietic progenitor cells (HPC) migrate to sites of allergic inflammation where, upon stimulation with epithelial cytokines, they produce Th2 cytokines and differentiate into mature eosinophils and basophils. They also express Toll-like receptors (TLR) involved in antimicrobial responses.
  
  
  OBJECTIVE
  The objective of this study was to compare TLR expression on peripheral blood HPC and TLR-induced responses, in particular changes in epithelial cytokine receptors, in healthy and asthmatic subjects at baseline and following allergen challenge.
  
  
  METHODS
  Ten healthy and 11 allergic asthmatic subjects were studied. HPC-enriched cell populations were stimulated with TLR-2, TLR-4 or TLR-9 ligands. TLR expression by circulating HPC and interleukin (IL)-25 (IL-17RB), IL-33 (ST2) and thymic stromal lymphopoietin receptor (TSLPR) expression after TLR ligation were examined by flow cytometry at baseline and, in asthmatics, following allergen challenge. The effects of dexamethasone (Dex) on TLR-induced responses were also assessed.
  
  
  RESULTS
  Asthmatics had significantly lower circulating HPC expressing TLR-2 and TLR-9 with a similar trend for TLR-4. TLR-4 stimulation of HPC yielded higher numbers of TSLPR+ cells in asthmatics compared with healthy subjects. A similar trend was seen for TLR-9 ligation, an effect further augmented by allergen inhalation. Allergen challenge also enhanced TLR-induced ST2 expression on HPC. Treatment with Dex in vitro increased TLR-4-induced TSLPR expression but had no effect on other epithelial cytokine receptors.
  
  
  CONCLUSIONS
  These data demonstrate an interaction between allergen and TLR ligand exposure in asthmatics. Allergen inhalation augments the TLR-induced inflammatory response by HPC, possibly leading to increased "in situ haemopoiesis" through up-regulation of TSLPR. These findings show that HPC may be a part of the pro-inflammatory cascade in pathogen-induced asthma exacerbation through their increased responsiveness to TLR stimulation.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Internal Diseases, Asthma and Allergy, Medical University of Lodz, Lodz, Poland.
authors.forename: D
authors.identifier: http://orcid.org/0000-0001-9862-6703
authors.initials: D
authors.lastname: Tworek
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Heroux
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: S N
authors.initials: SN
authors.lastname: O'Byrne
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: P M
authors.initials: PM
authors.lastname: O'Byrne
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Denburg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000485:Allergens / Q000276:immunology; D001249:Asthma / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D001491:Basophils / Q000276:immunology / Q000378:metabolism; D018592:Cross-Over Studies; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics*; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000485:Allergens; D016207:Cytokines; D018121:Receptors, Cytokine; D051193:Toll-Like Receptors
keywords: TSLPR; allergen challenge; asthma; epithelium; haemopoietic progenitor cells; innate immunity