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Sci Transl Med. 2017 Oct 18;9(412). pii: eaan5689. doi: 10.1126/scitranslmed.aan5689.

ALK is a therapeutic target for lethal sepsis.

Author information

1
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
2
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
3
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
4
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
5
Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
6
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China. tangd2@upmc.edu jiangjx@cta.cq.cn.
7
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong 510510, China. tangd2@upmc.edu jiangjx@cta.cq.cn.

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 tumor-associated 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.

PMID:
29046432
PMCID:
PMC5737927
DOI:
10.1126/scitranslmed.aan5689
[Indexed for MEDLINE]
Free PMC Article

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