坏死性下垂
肿瘤坏死因子α
肿瘤坏死因子受体1
炎症
交通2
表皮生长因子受体
癌症研究
MAPK/ERK通路
贸易
信号转导
生物
细胞生物学
免疫学
程序性细胞死亡
受体
医学
死亡域
细胞凋亡
内科学
肿瘤坏死因子受体
生物化学
作者
Huiling Zhang,Xuedi Zhang,Chunxiu Ling,Change Liu,Shaodong Hua,Ziying Xiong,Huimin Zhao,Qiushuang Feng,Zhichun Feng,Jing Tang,Xiaoyang Hong
标识
DOI:10.1016/j.intimp.2023.109902
摘要
Tumor necrosis factor-α (TNFα) 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-κB/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-κB/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.
科研通智能强力驱动
Strongly Powered by AbleSci AI