title: Myeloid differentiation factor 88-dependent signaling is critical for acute organic dust-induced airway inflammation in mice.
abstract: Organic dust exposure within agricultural environments results in airway diseases. Toll-like receptor 2 (TLR2) and TLR4 only partly account for the innate response to these complex dust exposures. To determine the central pathway in mediating complex organic dust-induced airway inflammation, this study targeted the common adaptor protein, myeloid differentiation factor 88 (MyD88), and investigated the relative contributions of receptors upstream from this adaptor. Wild-type, MyD88, TLR9, TLR4, IL-1 receptor I (RI), and IL-18R knockout (KO) mice were challenged intranasally with organic dust extract (ODE) or saline, according to an established protocol. Airway hyperresponsiveness (AHR) was assessed by invasive pulmonary measurements. Bronchoalveolar lavage fluid was collected to quantitate leukocyte influx and cytokine/chemokine (TNF-α, IL-6, chemokine [C-X-C motif] ligands [CXCL1 and CXCL2]) concentrations. Lung tissue was collected for histopathology. Lung cell apoptosis was determined by a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and lymphocyte influx and intercellular adhesion molecule-1 (ICAM-1) expression were assessed by immunohistochemistry. ODE-induced AHR was significantly attenuated in MyD88 KO mice, and neutrophil influx and cytokine/chemokine production were nearly absent in MyD88 KO animals after ODE challenges. Despite a near-absent airspace inflammatory response, lung parenchymal inflammation was increased in MyD88 KO mice after repeated ODE exposures. ODE-induced epithelial-cell ICAM-1 expression was diminished in MyD88 KO mice. No difference was evident in the small degree of ODE-induced lung-cell apoptosis. Mice deficient in TLR9, TLR4, and IL-18R, but not IL-1IR, demonstrated partial protection against ODE-induced neutrophil influx and cytokine/chemokine production. Collectively, the acute organic dust-induced airway inflammatory response is highly dependent on MyD88 signaling, and is dictated, in part, by important contributions from upstream TLRs and IL-18R.
authors.affiliation: Pulmonary, Critical Care, Sleep, and Allergy Division, Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bauer
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
authors.forename: Todd A
authors.initials: TA
authors.lastname: Wyatt
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Romberger
authors.forename: William W
authors.initials: WW
authors.lastname: West
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gleason
authors.forename: Jill A
authors.initials: JA
authors.lastname: Poole
mesh_terms: D000818:Animals; D017209:Apoptosis; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation; D004391:Dust / Q000276:immunology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D004391:Dust; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D018799:Intercellular Adhesion Molecule-1