title: Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice.
abstract: 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.
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Jihye
authors: J
authors: Han
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Joonbeom
authors: J
authors: Bae
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Chang-Yong
authors: CY
authors: Choi
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Sang-Pil
authors: SP
authors: Choi
authors: b School of Biological Sciences and Technology, Biotechnology Research Institute, Chonnam National University , Kwangju , Korea.
authors: Hyung-Sik
authors: HS
authors: Kang
authors: c Infection Signaling Network Research Center , Department of Microbiology , College of Medicine, Chungnam National University , Daejeon , Korea.
authors: Eun-Kyeong
authors: EK
authors: Jo
authors: d Department of Pharmacology , Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University , Daejeon , Korea.
authors: Jongsun
authors: J
authors: Park
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Young Sik
authors: YS
authors: Lee
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Hyun-Seuk
authors: HS
authors: Moon
authors: e Department of Microbiology and Immunology , Seoul National University College of Medicine , Seoul , Korea.
authors: Chung-Gyu
authors: CG
authors: Park
authors: f Severance Biomedical Science Institute , Department of Internal Medicine , College of Medicine, Yonsei University , Seoul , Korea.
authors: Myung-Shik
authors: MS
authors: Lee
authors: a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
authors: Taehoon
authors: T
authors: Chun
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000293:injuries* / Q000473:pathology*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D058847:Inflammasomes; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D008869:Microtubule-Associated Proteins; D048308:Mitogen-Activated Protein Kinase 14; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse; C492716:Nlrp3 protein, mouse; C000722290:AXL receptor tyrosine kinase, mouse
keywords: AXL receptor tyrosine kinase; NLRP3 inflammasome; autophagy; hepatic inflammation; macrophage