ALK is a therapeutic target for lethal sepsis

Ling Zeng, Rui Kang, Shan Zhu, Xiao Wang, Lizhi Cao, Haichao Wang, Timothy R. Billiar, Jianxin Jiang, Daolin Tang

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumorassociated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)-mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.

Original languageEnglish (US)
Article numbereaan5689
JournalScience Translational Medicine
Volume9
Issue number412
DOIs
StatePublished - Oct 18 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Zeng, L., Kang, R., Zhu, S., Wang, X., Cao, L., Wang, H., Billiar, T. R., Jiang, J., & Tang, D. (2017). ALK is a therapeutic target for lethal sepsis. Science Translational Medicine, 9(412), [eaan5689]. https://doi.org/10.1126/scitranslmed.aan5689