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, Youngsik Lee, Hyun-Seuk Moon, Chung Gyu Park, Myung Shik Lee, Taehoon Chun

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2326-2343
Number of pages18
JournalAutophagy
Volume12
Issue number12
DOIs
Publication statusPublished - 2016 Dec 1

Keywords

  • autophagy
  • AXL receptor tyrosine kinase
  • hepatic inflammation
  • macrophage
  • NLRP3 inflammasome

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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