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
Copyright policy )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
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.
- Case Western Reserve University United States
- University of California, San Francisco United States
Lipopolysaccharides, Biomedical and clinical sciences, Lipopolysaccharide Receptors, Inbred C57BL, Medical and Health Sciences, Cornea, Mice, Phosphorylation, Toll-like Receptors, Chemokine CCL5, Cells, Cultured, Mice, Knockout, Cultured, Blotting, Neutrophil, Intracellular Signaling Peptides and Proteins, Protein-Tyrosine Kinases, Biological Sciences, Endocytosis, Biological sciences, Infectious Diseases, Neutrophil Infiltration, Medical Microbiology, Pseudomonas aeruginosa, Host-Pathogen Interactions, Infection, Western, Biochemistry & Molecular Biology, 1.1 Normal biological development and functioning, Cells, Knockout, Blotting, Western, 610, Lipopolysaccharide, Cell Line, Underpinning research, 616, Syk Kinase, Animals, Humans, Pseudomonas Infections, Eye Disease and Disorders of Vision, Inflammation, Epithelial Cell, Biomedical and Clinical Sciences, Epithelial Cells, Interferon-beta, Toll-Like Receptor 4, Mice, Inbred C57BL, Chemical sciences, Chemical Sciences, Interferon Regulatory Factor-3
Lipopolysaccharides, Biomedical and clinical sciences, Lipopolysaccharide Receptors, Inbred C57BL, Medical and Health Sciences, Cornea, Mice, Phosphorylation, Toll-like Receptors, Chemokine CCL5, Cells, Cultured, Mice, Knockout, Cultured, Blotting, Neutrophil, Intracellular Signaling Peptides and Proteins, Protein-Tyrosine Kinases, Biological Sciences, Endocytosis, Biological sciences, Infectious Diseases, Neutrophil Infiltration, Medical Microbiology, Pseudomonas aeruginosa, Host-Pathogen Interactions, Infection, Western, Biochemistry & Molecular Biology, 1.1 Normal biological development and functioning, Cells, Knockout, Blotting, Western, 610, Lipopolysaccharide, Cell Line, Underpinning research, 616, Syk Kinase, Animals, Humans, Pseudomonas Infections, Eye Disease and Disorders of Vision, Inflammation, Epithelial Cell, Biomedical and Clinical Sciences, Epithelial Cells, Interferon-beta, Toll-Like Receptor 4, Mice, Inbred C57BL, Chemical sciences, Chemical Sciences, Interferon Regulatory Factor-3
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