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Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice

 Jihye Han  ;  Joonbeom Bae  ;  Chang-Yong Choi  ;  Sang-Pil Choi  ;  Hyung-Sik Kang  ;  Eun-Kyeong Jo  ;  Jongsun Park  ;  Young Sik Lee  ;  Hyun-Seuk Moon  ;  Chung-Gyu Park  ;  Myung-Shik Lee  ;  Taehoon Chun 
 AUTOPHAGY, Vol.12(12) : 2326-2343, 2016 
Journal Title
Issue Date
Animals ; Autophagy* ; Autophagy-Related Protein 5/genetics ; Autophagy-Related Protein 5/metabolism ; Beclin-1/genetics ; Beclin-1/metabolism ; Inflammasomes/metabolism* ; Intercellular Signaling Peptides and Proteins/metabolism ; Interleukin-18/biosynthesis ; Interleukin-1beta/biosynthesis ; Kupffer Cells/metabolism ; Kupffer Cells/pathology ; Liver/enzymology ; Liver/injuries* ; Liver/pathology* ; Macrophages/enzymology ; Macrophages/pathology ; Mice ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitogen-Activated Protein Kinase 14/metabolism ; Models, Biological ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Phosphorylation ; Protein Binding ; Protein Domains ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/deficiency ; Proto-Oncogene Proteins/metabolism* ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptor Protein-Tyrosine Kinases/chemistry ; Receptor Protein-Tyrosine Kinases/deficiency ; Receptor Protein-Tyrosine Kinases/metabolism* ; Signal Transduction
AXL receptor tyrosine kinase ; NLRP3 inflammasome ; autophagy ; hepatic inflammation ; macrophage
Severe hepatic inflammation is a common cause of acute or chronic liver disease. Macrophages are one of the key mediators which regulate the progress of hepatic inflammation. Increasing evidence shows that the TAM (TYRO3, AXL and MERTK) family of RTKs (receptor tyrosine kinases), which is expressed in macrophages, alleviates inflammatory responses through a negative feedback loop. However, the functional contribution of each TAM family member to the progression of hepatic inflammation remains elusive. In this study, we explore the role of individual TAM family proteins during autophagy induction and evaluate their contribution to hepatic inflammation. Among the TAM family of RTKs, AXL (AXL receptor tyrosine kinase) only induces autophagy in macrophages after interaction with its ligand, GAS6 (growth arrest specific 6). Based on our results, autophosphorylation of 2 tyrosine residues (Tyr815 and Tyr860) in the cytoplasmic domain of AXL in mice is required for autophagy induction and AXL-mediated autophagy induction is dependent on MAPK (mitogen-activated protein kinase)14 activity. Furthermore, induction of AXL-mediated autophagy prevents CASP1 (caspase 1)-dependent IL1B (interleukin 1, β) and IL18 (interleukin 18) maturation by inhibiting NLRP3 (NLR family, pyrin domain containing 3) inflammasome activation. In agreement with these observations, axl-/- mice show more severe symptoms than do wild-type (Axl+/+) mice following acute hepatic injury induced by administration of lipopolysaccharide (LPS) or carbon tetrachloride (CCl4). Hence, GAS6-AXL signaling-mediated autophagy induction in murine macrophages ameliorates hepatic inflammatory responses by inhibiting NLRP3 inflammasome activation.
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Yonsei Authors
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
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