ALK is a therapeutic target for lethal 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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“…The subjects were not involved in previous procedures and test naïve. Clinical characteristics of sepsis patients and healthy control individuals including sex and age are shown in our previous publication (Table S1) (Zeng et al, 2017). Collection of samples was approved by the Institutional Review Board.…”

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“…fig. 6) as were ALK and AMPK (#7 and #17), two kinases that have been proposed as STING pathway regulators (29,30,31). To focus on novel kinases, we removed compounds with known activities against TBK1 and re-ran enrichment.…”

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