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

• Published in: Autophagy 2016-12, Vol.12 (12), p.2326-2343
• Main Authors: Han, Jihye, Bae, Joonbeom, Choi, Chang-Yong, Choi, Sang-Pil, Kang, Hyung-Sik, Jo, Eun-Kyeong, Park, Jongsun, Lee, Young Sik, Moon, Hyun-Seuk, Park, Chung-Gyu, Lee, Myung-Shik, Chun, Taehoon
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; AXL receptor tyrosine kinase; Basic Research Paper; Beclin-1 - genetics; Beclin-1 - metabolism; hepatic inflammation; 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; macrophage; 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; NLRP3 inflammasome; Phosphorylation; Protein Binding; Protein Domains; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - chemistry; Receptor Protein-Tyrosine Kinases - deficiency; Receptor Protein-Tyrosine Kinases - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2016.1235124

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 (CCl 4 ). Hence, GAS6-AXL signaling-mediated autophagy induction in murine macrophages ameliorates hepatic inflammatory responses by inhibiting NLRP3 inflammasome activation.