title: Toll-like receptor 2 regulates organic dust-induced airway inflammation.
abstract: Organic dust exposure in agricultural environments results in significant airway inflammatory diseases. Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating dust-induced airway inflammation is not clear. This study investigated the role of Toll-like receptor (TLR) 2, a pattern recognition receptor for gram-positive cell wall products, in regulating swine facility organic dust extract (DE)-induced airway inflammation in mice. Isolated lung macrophages from TLR2 knockout mice demonstrated reduced TNF-α, IL-6, keratinocyte chemoattractant/CXCL1, but not macrophage inflammatory protein-2/CXCL2 expression, after DE stimulation ex vivo. Next, using an established mouse model of intranasal inhalation challenge, we analyzed bronchoalveolar lavage fluid and lung tissue in TLR2-deficient and wild-type (WT) mice after single and repetitive DE challenge. Neutrophil influx and select cytokines/chemokines were significantly lower in TLR2-deficient mice at 5 and 24 hours after single DE challenge. After daily exposure to DE for 2 weeks, there were significant reductions in total cellularity, neutrophil influx, and TNF-α, IL-6, CXCL1, but not CXCL2 expression, in TLR2-deficient mice as compared with WT animals. Lung pathology revealed that bronchiolar inflammation, but not alveolar inflammation, was reduced in TLR2-deficient mice after repetitive exposure. Airway hyperresponsiveness to methacholine after dust exposure was similar in both groups. Finally, airway inflammatory responses in WT mice after challenge with a TLR2 agonist, peptidoglycan, resembled DE-induced responses. Collectively, these results demonstrate that the TLR2 pathway is important in regulating swine facility organic dust-induced airway inflammation, which suggests the importance of TLR2 agonists in mediating large animal farming-induced airway inflammatory responses.
authors.affiliation: Omaha Veterans Affairs Medical Center, Omaha, Nebraska, USA. japoole@unmc.edu
authors.forename: Jill A
authors.initials: JA
authors.lastname: Poole
authors.forename: Todd A
authors.initials: TA
authors.lastname: Wyatt
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
authors.forename: Peter
authors.initials: P
authors.lastname: Oldenburg
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gleason
authors.forename: Ashley
authors.initials: A
authors.lastname: Bauer
authors.forename: Gregory
authors.initials: G
authors.lastname: Golden
authors.forename: William W
authors.initials: WW
authors.lastname: West
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Sisson
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Romberger
mesh_terms: D000822:Animal Husbandry; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004391:Dust; D006799:Housing, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000276:immunology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control; D013552:Swine; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016085:Bronchoconstrictor Agents; D018925:Chemokines; D016207:Cytokines; D004391:Dust; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010457:Peptidoglycan; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016210:Methacholine Chloride; D009569:Nitric Oxide