Research ArticleSepsis

ALK is a therapeutic target for lethal sepsis

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Science Translational Medicine  18 Oct 2017:
Vol. 9, Issue 412, eaan5689
DOI: 10.1126/scitranslmed.aan5689

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Taking the STING out of sepsis

Despite the existence of antibiotic therapy, sepsis is associated with a high mortality rate. Zeng et al. screened a library of kinase inhibitors to identify drugs that targeted the STING (stimulator of interferon genes) pathway, which was up-regulated in mononuclear cells from patients with sepsis. The authors found that STING is activated by anaplastic lymphoma kinase (ALK), which interacts with epidermal growth factor receptor and signals through downstream serine-threonine protein kinase AKT. Inhibiting ALK-STING signaling genetically or with oral drug treatment improved survival in mouse models of sepsis and endotoxemia. The ALK-STING pathway could be a useful target for drug development for sepsis.

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.

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