EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis

Abstract

EGFR phosphorylation is required for TLR4-mediated macrophage activation during sepsis. However, whether and how intracellular EGFR is transported during endotoxemia have largely been unknown. Here, we show that LPS promotes high levels cell surface expression of EGFR in macrophages through two different transport mechanisms. On one hand, Rab10 is required for EEA1-mediated the membrane translocation of EGFR from the Golgi. On the other hand, EGFR phosphorylation prevents its endocytosis in a kinase activity-dependent manner. Erlotinib, an EGFR tyrosine kinase inhibitor, significantly reduced membrane EGFR expression in LPS-activated macrophage. Mechanistically, upon LPS induced TLR4/EGFR phosphorylation, MAPK14 phosphorylated Rab7a at S72 impaired membrane receptor late endocytosis, which maintains EGFR membrane localization though blocking its lysosomal degradation. Meanwhile, Rab5a is also involved in the early endocytosis of EGFR. Subsequently, inhibition of EGFR phosphorylation switches M1 phenotype to M2 phenotype and alleviates sepsis-induced acute lung injury. Mechanistic study demonstrated that Erlotinib suppressed glycolysis-dependent M1 polarization via PKM2/HIF-1ɑ pathway and promoted M2 polarization through up-regulating PPARγ induced glutamine metabolism. Collectively, our data elucidated a more in-depth mechanism of macrophages activation, and provided stronger evidence supporting EGFR as a potential therapeutic target for the treatment of sepsis.

Mechanism and Experimental Verification of Rhodiola rosea L. for the Treatment of Acute Lung Injury Through Network Pharmacology and Molecular Docking

“…35 In the rat model of ALI, the MAPK signaling pathway was also involved, thus limiting the development of inflammation and downregulating IL-6 and TNF-α secretion. 36 Research has confirmed that in the sepsis-induced ALI rats, inhibiting EGFR phosphorylation converts the M1 phenotype of macrophages into the M2 phenotype, which reduces ALI, 37 Meanwhile, EGFR was significantly activated. When EGFR is inhibited, it can limit the permeability of pulmonary blood vessels and neutrophils.…”

Cell-Vision Fusion: A Swin Transformer-based Approach to Predicting Kinase Inhibitor Mechanism of Action from Cell Painting Data

“…PI3K can also disrupt the actin cytoskeleton 56 , while both contribute to actin filament remodelling throughout the cell 57,58 . EGFR is also highly connected to the functioning of the Golgi apparatus in protein transport 59,60 and is a plasma membrane receptor. Comparatively, PI3K-generated PIP3 is localized to the plasma membrane and is involved in protein kinase localization and activation as well as the EGFR regulation of membrane ruffling 61 .…”

Anti-cancer effects of bis-oxidized thiopyran derivatives on non-small cell lung cancer: rational design, synthesis, and activity evaluation

“…22–24 The problem of resistance to the previous EGFR-TKIs in advanced NSCLC patients with EGFR gene-sensitive mutations is solved, and adverse reactions are reduced. 25,26 Osimertinib ( AZD9291 ) is a third-generation EGFR-TKI developed by AstraZeneca in 2015 and has been quickly used in the first-line treatment of NSCLC due to its efficacy and low toxicity in patients with advanced NSCLC. 27–30 It is a highly bioavailable third-generation irreversible inhibitor with strong therapeutic effects against EGFR L858R and EGFR T790M and low affinity for the wild-type EGFR.…”