Page 42 - M. Immunology

[M. Immunology-27]

AXL receptor tyrosine kinase-induced autophagy ameliorates

acute liver injury by suppressing NLRP3 inflammasome

activation in mice

Si-Won Park¹, Taehoon Chun¹˙*

¹Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea

Liver disease is commonly caused by severe hepatic inflammation and macrophages are one of the key regulators
of inflammatory responses. Various evidence supports that the TAM (TYRO3, AXL and MERTK) family of RTKs
(receptor tyrosine kinases), expressed in macrophages, negatively regulates inflammation. Here, we investigate the

contribution of each TAM family protein to autophagy induction and hepatic inflammation. AXL (AXL receptor
tyrosine kinase), one of the TAM family of RTKs, only induces autophagy in macrophages after binding to its ligand,

GAS6 (growth arrest specific 6). Our results indicate that autophosphorylation of 2 tyrosine residues in the
cytoplasmic domain of AXL is essential for autophagy induction and AXL-mediated autophagy relies on MAPK

(mitogen-activated protein kinase)14 activity. In addition, suppression of NLRP3 (NLR family, pyrin domain containing
3) inflammasome activation causes AXL-induced autophagy to inhibit CASP1 (caspase 1)-dependent IL1B and IL18

maturation. Also, in response to acute hepatic injury induced by treatment with LPS or CCl4, axl−/− mice show
more serious symptoms than do wild-type mice. Consequently, autophagy induction mediated by GAS6-AXL

signaling alleviates hepatic inflammation via repression of NLRP3 inflammasome activation.