FAK mediates LPS-induced inflammatory lung injury through interacting TAK1 and activating TAK1-NFκB pathway.

Abstract

Acute lung injury (ALI), characterized by inflammatory damage, is a major clinical challenge. Developing specific treatment options for ALI requires the identification of novel targetable signaling pathways. Recent studies reported that endotoxin lipopolysaccharide (LPS) induced a TLR4-dependent activation of focal adhesion kinase (FAK) in colorectal adenocarcinoma cells, suggesting that FAK may be involved in LPS-induced inflammatory responses. Here, we investigated the involvement and mechanism of FAK in mediating LPS-induced inflammation and ALI. We show that LPS phosphorylates FAK in macrophages. Either FAK inhibitor, site-directly mutation, or siRNA knockdown of FAK significantly suppresses LPS-induced inflammatory cytokine production in macrophages. FAK inhibition also blocked LPS-induced activation of MAPKs and NFκB. Mechanistically, we demonstrate that activated FAK directly interacts with transforming growth factor-β-activated kinase-1 (TAK1), an upstream kinase of MAPKs and NFκB, and then phosphorylates TAK1 at Ser412. In a mouse model of LPS-induced ALI, pharmacological inhibition of FAK suppressed FAK/TAK activation and inflammatory response in lung tissues. These activities resulted in the preservation of lung tissues in LPS-challenged mice and increased survival during LPS-induced septic shock. Collectively, our results illustrate a novel FAK-TAK1-NFκB signaling axis in LPS-induced inflammation and ALI, and support FAK as a potential target for the treatment of ALI.

• Authors: Xi Chen, Ying Zhao, Xu Wang, Yimin Lin, Weixin Zhao, Di Wu, Jingye Pan, Wu Luo, Yi Wang, Guang Liang
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 7 Pg. 589 (07 08 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35803916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Lipopolysaccharides
• NF-kappa B
• Focal Adhesion Protein-Tyrosine Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Acute Lung Injury (chemically induced, metabolism)
• Animals
• Focal Adhesion Protein-Tyrosine Kinases
• Inflammation (pathology)
• Lipopolysaccharides
• MAP Kinase Kinase Kinases (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)