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

Abstract

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-b (IFN-b) and IFN-inducible genes is strongly inhibited, whereas TNF-a 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 b-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.

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

“…EGFR signaling has been shown to mediate lipopolysaccharide-induced inflammation via regulating the activation of nuclear factor-κB (NF-κB) in macrophages18. Given that EGFR inhibitors 452 and AG1478 are able to attenuate atherosclerosis through reducing inflammation in mice, we investigated the anti-inflammatory effects of EGFR inhibitors in oxidized-LDL (ox-LDL)-stimulated primary macrophages.…”

“…S11a). As macrophage NF-κB18 has been shown to be critical in inflammation, we assessed its activation by western blotting and cell staining. Our results show increased NF-κB p65 subunit in the nuclear protein fraction and increased nuclear staining of macrophages stimulated by ox-LDL, as detected by western bott method (Fig.…”

“…EGFR activation by metalloproteinase meprin-α mediates ox-LDL-induced oxidative stress in macrophages15. Furthermore, EGFR leads to downstream activation of transcription factors such as nuclear factor-κB (NF-κB) and stimulates pro-inflammatory gene transcription in macrophages161718. Recent findings have also suggested that EGF-like ligands may serve as biomarkers for active inflammatory atherosclerosis in a primate model of atherosclerosis19.…”

Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

“…Gefitinib and erlotinib reduce pulmonary damage and promote increased survival in mouse models of sepsis, 20,21 while erlotinib blunts the proinflammatory and proliferative responses following hepatic injury.…”

“…[22][23][24][25] Linkages, however, are unclear and interactions between TLR4 and EGFR may be functional as complexes between the two receptors have not been detected. 20,21 Integrins are also implicated in pathogen-induced TLR activation; such cooperation occurs in both immune and nonimmune cells where integrins enhance the innate immune response. Certain integrins may serve as TLR coreceptors, binding directly to ligands to initiate TLR signaling.…”