title: Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung.
abstract: Toll-like receptors (TLRs) have been implicated in the regulation of host responses to microbial Ags. This study characterizes the role of TLR4 in the innate immune response to intrapulmonary administration of Haemophilus influenzae in the mouse. Two different strains of mice efficiently cleared aerosolized H. influenzae concurrent with a brisk elaboration of IL-1beta, IL-6, TNF-alpha, macrophage-inflammatory protein (MIP)-1alpha, and MIP-2 in bronchoalveolar lavage and a corresponding mobilization of intrapulmonary neutrophils. Congenic strains of mice deficient in TLR4 demonstrated a substantial delay in clearance of H. influenzae with diminished IL-1beta, IL-6, TNF-alpha, MIP-1alpha, and MIP-2 in bronchoalveolar lavage and a notable absence of intrapulmonary neutrophils. In TLR4-expressing animals, but not TLR4-deficient animals, TNF-alpha and MIP-1alpha expression was up-regulated in epithelial cells of the conducting airway in response to H. influenzae which was preceded by an apparent activation of the NF-kappaB pathway in these cells based on the findings of decreased overall IkappaB and an increase in its phosphorylated form. This study demonstrates a critical role of TLR4 in mediating an effective innate immune response to H. influenzae in the lung. This suggests that the airway epithelia might contribute to sensing of H. influenzae infection and signaling the innate immune response.
authors.affiliation: Institute for Human Gene Therapy, Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Moser
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Louboutin
authors.forename: Elena S
authors.initials: ES
authors.lastname: Lysenko
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weiner
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D006192:Haemophilus Infections / Q000276:immunology* / Q000473:pathology; D006193:Haemophilus influenzae / Q000276:immunology*; D020672:I-kappa B Proteins; D007113:Immunity, Innate / Q000235:genetics; D007150:Immunohistochemistry; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha