EGFR-TNFR1 pathway in endothelial cell facilitates acute lung injury by NF-ΚB/MAPK-mediated inflammation and RIP3-dependent necroptosis

Tumor necrosis factor-alpha (TNF alpha) has emerged as a pivotal effector critically correlated with disease severity in acute lung injury (ALI). Because both the excessive activation of epidermal growth factor receptor (EGFR) and tumor necrosis factor receptor 1 (TNFR1) in sepsis-induced vasculitis are markedly diminished through EGFR tyrosine kinase inhibitor, a specific mechanism must exist to modulate TNFR1 cellular fates regulated by EGFR. Here, we demonstrated that EGFR, a specific binding partner of TNFR1, exhibited an increased NF-kappa B/MAPK-mediated inflammation that was governed by enhanced recruitment of TNFR-associated factor 2 (TRAF2) to TNFR1 complex I in endothelial cell (EC). Moreover, EGFR activation triggered a remarkable increase in the phosphorylation of receptor-interacting protein 1 (RIP1) and its binding with receptor-interacting protein 3 (RIP3) which led to enhanced frequency of necroptosis in complex IIb. Inhibiting the kinase of EGFR disrupted the formation of complex I and complex IIb and prevents EC from NF-kappa B/MAPK-mediated inflammation and RIP3-dependent necroptosis. Consistently, pharmacological inhibition of EGFR can limit the destructive effects of neutrophils activation and the hyperpermeability of lung vascular in hyperinflammation period. Collectively, we have identified EC-EGFR as a modulator of TNFR1-mediated inflammation and RIP3-dependent necroptosis, providing a possible explanation for the immunological basis of anti-EGFR therapy in sepsis-induced ALI.

Automated summary

EGFR is a specific binding partner of TNFR1 and enhances NF-kappa B/MAPK-mediated inflammation by recruiting TRAF2 to TNFR1 complex I in endothelial cells. EGFR activation also promotes necroptosis by increasing the phosphorylation of RIP1 and its binding with RIP3 in complex IIb. Inhibiting EGFR disrupts the formation of complex I and complex IIb, preventing inflammation and necroptosis. Pharmacological inhibition of EGFR can limit neutrophil activation and lung vascular hyperpermeability. These findings provide an immunological basis for anti-EGFR therapy in sepsis-induced acute lung injury.