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
a Department of Biotechnology , College of Life Sciences and Biotechnology, Korea University , Seoul , Korea.
b School of Biological Sciences and Technology, Biotechnology Research Institute, Chonnam National University , Kwangju , Korea.
Autophagy. 2016 Dec;12(12):2326-2343. 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). Hence, GAS6-AXL signaling-mediated autophagy induction in murine macrophages ameliorates hepatic inflammatory responses by inhibiting NLRP3 inflammasome activation.
严重的肝脏炎症是急性或慢性肝病的常见病因。巨噬细胞是调节肝脏炎症进展的关键介质之一。越来越多的证据表明，在巨噬细胞中表达的受体酪氨酸激酶（RTK）的TAM（TYRO3、AXL和MERTK）家族通过负反馈回路减轻炎症反应。然而，每个TAM家族成员对肝脏炎症进展的功能贡献仍不清楚。在本研究中，我们探讨了单个TAM家族蛋白在自噬诱导过程中的作用，并评估了它们对肝脏炎症的贡献。在RTK的TAM家族中，AXL（AXL受体酪氨酸激酶）仅在与其配体GAS6（生长停滞特异性6）相互作用后在巨噬细胞中诱导自噬。根据我们的结果，小鼠AXL胞质结构域中2个酪氨酸残基（Tyr815和Tyr860）的自磷酸化是自噬诱导所必需的，并且AXL介导的自噬诱导依赖于丝裂原活化蛋白激酶（MAPK）14的活性。此外，AXL介导的自噬诱导通过抑制NLRP3（含pyrin结构域的NLR家族3）炎性小体活化来阻止半胱天冬酶1（CASP1）依赖性白细胞介素1β（IL1B）和白细胞介素18（IL18）的成熟。与这些观察结果一致，在给予脂多糖（LPS）或四氯化碳（CCl）诱导急性肝损伤后，axl小鼠比野生型（Axl）小鼠表现出更严重的症状。因此，GAS6-AXL信号介导的小鼠巨噬细胞自噬诱导通过抑制NLRP3炎性小体活化来改善肝脏炎症反应。
