EGFR kinase activity is required for TLR4 signaling and the septic shock response

Mammalian Toll‐like receptors (TLR) recognize microbial products and elicit transient immune responses that protect the infected host from disease. TLR4—which signals from both plasma and endosomal membranes—is activated by bacterial lipopolysaccharides (LPS) and induces many cytokine genes, the pro...

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Bibliographic Details
Published in:EMBO reports 2015-11, Vol.16 (11), p.1535-1547
Main Authors: Chattopadhyay, Saurabh, Veleeparambil, Manoj, Poddar, Darshana, Abdulkhalek, Samar, Bandyopadhyay, Sudip K, Fensterl, Volker, Sen, Ganes C
Format: Article
Language:English
Subjects:
AKT
Animals
EGFR
Epidermal growth factor
Interferon Regulatory Factors - metabolism
Interferon-beta - genetics
Interferon-beta - metabolism
IRF
Kinases
Lipopolysaccharides - administration & dosage
Mice
Microarray Analysis
Myeloid Cells - metabolism
NF-kappa B - metabolism
Pathology
Phosphatidylinositol 3-Kinases - metabolism
PI3 Kinase
Protein Kinase Inhibitors - pharmacology
Quinazolines - pharmacology
RAW 264.7 Cells
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - metabolism
Sepsis
septic shock
Shock, Septic - metabolism
Shock, Septic - prevention & control
Shock, Septic - therapy
Signal Transduction - drug effects
TLR
Toll-Like Receptor 4 - metabolism
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
β-catenin
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Summary:Mammalian Toll‐like receptors (TLR) recognize microbial products and elicit transient immune responses that protect the infected host from disease. TLR4—which signals from both plasma and endosomal membranes—is activated by bacterial lipopolysaccharides (LPS) and induces many cytokine genes, the prolonged expression of which causes septic shock in mice. We report here that the expression of some TLR4‐induced genes in myeloid cells requires the protein kinase activity of the epidermal growth factor receptor (EGFR). EGFR inhibition affects TLR4‐induced responses differently depending on the target gene. The induction of interferon‐β (IFN‐β) and IFN‐inducible genes is strongly inhibited, whereas TNF‐α induction is enhanced. Inhibition is specific to the IFN‐regulatory factor (IRF)‐driven genes because EGFR is required for IRF activation downstream of TLR—as is IRF co‐activator β‐catenin—through the PI3 kinase/AKT pathway. Administration of an EGFR inhibitor to mice protects them from LPS‐induced septic shock and death by selectively blocking the IFN branch of TLR4 signaling. These results demonstrate a selective regulation of TLR4 signaling by EGFR and highlight the potential use of EGFR inhibitors to treat septic shock syndrome. Synopsis This study shows that EGFR kinase activity is necessary for the induction of interferon‐dependent, TLR4‐responsive genes. EGFR inhibition in vivo blocks septic shock and prevents death, suggesting a therapeutic avenue for this important pathology. EGFR kinase activity differentially regulates TLR4‐induced gene expression. EGFR activity is required for IRF activation. EGFR activity is required for PI3K/AKT‐dependent phosphorylation of β‐catenin, a co‐activator of IRF3. In vivo administration of an EGFR kinase inhibitor protects mice from LPS‐induced septic shock. This study shows that EGFR kinase activity is necessary for the induction of interferon‐dependent, TLR4‐responsive genes. EGFR inhibition in vivo blocks septic shock and prevents death, suggesting a therapeutic avenue for this important pathology.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201540337