| First Author | Zeng L | Year | 2017 |
| Journal | Sci Transl Med | Volume | 9 |
| Issue | 412 | PubMed ID | 29046432 |
| Mgi Jnum | J:248299 | Mgi Id | MGI:5918633 |
| Doi | 10.1126/scitranslmed.aan5689 | Citation | Zeng L, et al. (2017) ALK is a therapeutic target for lethal sepsis. Sci Transl Med 9(412) |
| abstractText | 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 kappaB (NF-kappaB) 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. |
