title: CD14 mediates Toll-like receptor 4 (TLR4) endocytosis and spleen tyrosine kinase (Syk) and interferon regulatory transcription factor 3 (IRF3) activation in epithelial cells and impairs neutrophil infiltration and Pseudomonas aeruginosa killing in vivo.
abstract: In the current study, we examined the role of CD14 in regulating LPS activation of corneal epithelial cells and Pseudomonas aeruginosa corneal infection. Our findings demonstrate that LPS induces Toll-like receptor 4 (TLR4) internalization in corneal epithelial cells and that blocking with anti-CD14 selectively inhibits TLR4 endocytosis, spleen tyrosine kinase (Syk) and IRF3 phosphorylation, and production of CCL5/RANTES and IFN-β, but not IL-8. Using a murine model of P. aeruginosa corneal infection, we show that although infected CD14(-/-) corneas produce less CCL5, they exhibit significantly increased CXC chemokine production, neutrophil recruitment to the corneal stroma, and bacterial clearance than C57BL/6 mice. We conclude that CD14 has a critical role in mediating TLR4 signaling through IRF3 in resident corneal epithelial cells and macrophages and thereby modulates TLR4 cell surface activation of the MyD88/NF-κB/AP-1 pathway and production of CXC chemokines and neutrophil infiltration to infected tissues.
authors.affiliation: From the Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44095.
authors.forename: Sanhita
authors.initials: S
authors.lastname: Roy
authors.forename: Mausita
authors.initials: M
authors.lastname: Karmakar
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D003315:Cornea / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000502:physiology; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse
keywords: Cornea; Epithelial Cell; Inflammation; Lipopolysaccharide (LPS); Neutrophil; Pseudomonas aeruginosa; Toll-like Receptors (TLRs)