title: The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A.
abstract: TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus-induced and house dust mite antigen-induced (HDM antigen-induced) chronic asthma. Tlr6-/- mice with fungal- or HDM antigen-induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6-/- versus WT asthmatic mice. Tlr6-/- DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6-/- mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic Tlr6-/- mice restored IL-17A production and substantially reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with that in untreated asthmatic Tlr6-/- mice. Together, our data demonstrate that TLR6 activation is critical for IL-23 production and Th17 responses, which both regulate the allergic inflammatory response in chronic fungal-induced asthma. Thus, therapeutics targeting TLR6 activity might prove efficacious in the treatment of clinical asthma.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA. anapaula@umich.edu
authors: Ana Paula
authors: AP
authors: Moreira
authors: Karen A
authors: KA
authors: Cavassani
authors: Ugur B
authors: UB
authors: Ismailoglu
authors: Rikki
authors: R
authors: Hullinger
authors: Michael P
authors: MP
authors: Dunleavy
authors: Darryl A
authors: DA
authors: Knight
authors: Steven L
authors: SL
authors: Kunkel
authors: Satoshi
authors: S
authors: Uematsu
authors: Shizuo
authors: S
authors: Akira
authors: Cory M
authors: CM
authors: Hogaboam
mesh_terms: D000403:Airway Resistance / Q000276:immunology; D000818:Animals; D001232:Aspergillus fumigatus / Q000472:pathogenicity; D001249:Asthma / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D053760:Interleukin-23 Subunit p19 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D039981:Pyroglyphidae / Q000472:pathogenicity; D051192:Receptors, Pattern Recognition / Q000502:physiology; D051216:Toll-Like Receptor 6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D051192:Receptors, Pattern Recognition; C495368:TLR6 protein, human; C495369:Tlr6 protein, mouse; D051216:Toll-Like Receptor 6