title: Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung.
abstract: The lung is colonized by commensal bacteria, some of which are associated with asthma exacerbations. Using the intranasal house-dust mite-sensitized mouse model of allergic airway disease, we show an imbalance in novel antibacterial pathways that culminates in a reduction in neutrophil recruitment to the airspaces and leads to bacterial invasion and dissemination. The expression of TREM (Triggering Receptor Expressed on Myeloid cells)-1 that amplifies Toll-like receptor (TLR) signaling and TREM-2 that inhibits this process is reversed. Furthermore, endogenous TLR inhibitors (A20, Tollip, SOCS1, and IRAK-M) and proteins involved in receptor recycling (TRIAD3) are raised. Consequently, the production of neutrophil chemoattractants is reduced. Intranasal administration of either chemokine restores the ability to recruit neutrophils, which prevents bacterial invasion. A background of allergic airway disease therefore exacerbates bacterial infection by altering key antibacterial innate immune pathways that are amenable to therapeutic intervention.
authors.affiliation: Imperial College London, Leukocyte Biology Section, National Heart and Lung Institute, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Habibzay
authors.forename: J I
authors.initials: JI
authors.lastname: Saldana
authors.forename: J
authors.initials: J
authors.lastname: Goulding
authors.forename: C M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: T
authors.initials: T
authors.lastname: Hussell
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D011008:Pneumococcal Infections / Q000150:complications / Q000276:immunology*; D039981:Pyroglyphidae / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000276:immunology*; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D039741:Antigens, Dermatophagoides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D051193:Toll-Like Receptors; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1