Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA, USA.
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
Life Sci Alliance. 2020 Jun 22;3(8). doi: 10.26508/lsa.202000694. Print 2020 Aug.
Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.
全基因组关联研究表明 TAM 受体酪氨酸激酶 (RTK) Mer 与肝脏疾病有关，但我们对 Mer 及其相关 RTKs Tyro3 和 Axl 在肝脏稳态和对急性损伤的反应中的作用的了解有限。我们发现 Mer 和 Axl 在肝库普弗细胞和内皮细胞中表达最为显著，而当缺乏这些 RTKs 的小鼠衰老时，它们会发展为特征为凋亡细胞积累和免疫激活的严重肝脏疾病。我们进一步发现，Mer 对于清除急性肝损伤时产生的凋亡肝细胞的吞噬作用至关重要，并且 Mer 和 Axl 在这些情况下协同作用以抑制细胞因子的产生。相比之下，我们发现 Axl 在对乙酰氨基酚中毒期间减轻肝损伤方面具有独特的重要性。尽管 Mer 和 Axl 在急性损伤模型中具有保护作用，但我们发现 Axl 在慢性损伤模型中加剧了纤维化。这些不同的影响对于设计和实施 TAM 靶向治疗具有重要意义，这些治疗可能会在肝脏中靶向这些 RTKs。
