title: Absence of Toll-IL-1 receptor 8/single immunoglobulin IL-1 receptor-related molecule reduces house dust mite-induced allergic airway inflammation in mice.
abstract: Allergic asthma is a chronic inflammatory disease predominately associated with the activation of CD4(+) T helper Type 2 (Th2) cells. Innate pattern recognition receptors are widely acknowledged to shape the adaptive immune response. For example, the activation of airway epithelial Toll-like receptor-4 (TLR4) is necessary for the generation of house dust mite (HDM)-specific Th2 responses and the development of asthma in mice. Here we sought to determine whether the absence of Toll-interleukin-1 receptor (TIR)-8, a negative regulator of TLR4 signaling that is highly expressed in airway epithelial cells, would exacerbate HDM-induced asthma in a murine model. We found that Th2 but not Th1 or Th17 cytokine expression was significantly reduced in the lung and draining lymph nodes in HDM-sensitized/challenged TIR8 gene-deleted mice. Mucus-producing goblet cells, HDM-specific IgG1, and airway hyperreactivity were also significantly reduced in HDM-exposed, TIR8-deficient mice. Consistent with the attenuated Th2 response, eotaxin-2/CCL24 expression and airway and peribronchial eosinophils were significantly reduced in the absence of TIR8. In contrast, IL-17A-responsive chemokines and neutrophil numbers were unaffected. Similar findings were obtained for cockroach allergen. HDM sensitization alone up-regulated the expression of IL-1F5, a putative TIR8 ligand and inducer of IL-4. Of note, innate IL-4, IL-5, IL-13, and IL-33 cytokine expression was reduced during HDM sensitization in the absence of TIR8, as was the recruitment of conventional dendritic cells and basophils to the draining lymph nodes. Our findings suggest that TIR8 enhances the development of HDM-induced innate and adaptive Th2, but not Th1 or Th17 type immunity.
authors.affiliation: Centre for Asthma and Respiratory Diseases and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Barry
authors.forename: Zhixuan
authors.initials: Z
authors.lastname: Loh
authors.forename: Adam
authors.initials: A
authors.lastname: Collison
authors.forename: Stuart
authors.initials: S
authors.lastname: Mazzone
authors.forename: Amit
authors.initials: A
authors.lastname: Lalwani
authors.forename: Vivian
authors.initials: V
authors.lastname: Zhang
authors.forename: Sophia
authors.initials: S
authors.lastname: Davidson
authors.forename: Elisha
authors.initials: E
authors.lastname: Wybacz
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
mesh_terms: D056704:Adaptive Immunity; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000276:immunology*; D054423:Chemokine CCL24 / Q000235:genetics / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D019476:Insect Proteins / Q000008:administration & dosage / Q000276:immunology*; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; C097505:Blatella germanica allergen 4; C515485:Ccl24 protein, mouse; D054423:Chemokine CCL24; C478197:Il36rn protein, mouse; D007074:Immunoglobulin G; D019476:Insect Proteins; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse