ALK is a therapeutic target for lethal sepsis

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

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.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Cecum / pathology
  • Endotoxemia / immunology
  • Endotoxemia / pathology
  • ErbB Receptors / metabolism
  • Female
  • Gene Silencing / drug effects
  • Humans
  • Ligation
  • Lipopolysaccharides
  • Male
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-akt / metabolism
  • Punctures
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Sepsis / prevention & control

Substances

  • Lipopolysaccharides
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • Sting1 protein, mouse
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt