These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver

These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver. Introduction Liver diseasesincluding acute liver failure, viral hepatitis, and alcoholic and nonalcoholic fatty liver disease (NAFLD)represent a major medical burden worldwide (Stravitz & Kramer, 2009; Corey & Kaplan, 2014; Louvet & Mathurin, 2015). and alcoholic and nonalcoholic fatty liver disease (NAFLD)represent a major medical burden worldwide (Stravitz & Kramer, 2009; Corey & Kaplan, 2014; Louvet & Mathurin, 2015). Increasing evidence suggests that both progression and resolution of these diseases depend around the kinetics and intensity of innate and adaptive immune responses CD200 (Sipeki et al, 2014; Guidotti et al, 2015) and that macrophagesincluding Kupffer cells (KCs), the resident macrophages of the liverare important NSC632839 regulation loci (Smith, 2013). We have shown that this TAM receptor tyrosine kinases (RTKs)Tyro3, Axl, and Mer (Lemke, 2013)are pivotal modulators of tissue macrophage function generally (Lu & Lemke, 2001; Rothlin et al, 2007; Zagrska et al, 2014; Dransfield et al, 2015; Fourgeaud et al, 2016; Lemke, 2019). Over the last several years, genome-wide association studies have tied polymorphisms in the human geneencoding Merto altered risk for both (a) fibrosis in patients with chronic hepatitis C computer virus contamination (Patin et al, 2012; Rueger et al, 2014; Matsuura & Tanaka, 2016; Jimenez-Sousa et al, 2018) and (b) NAFLD, in which two intronic single-nucleotide polymorphisms are protective (Petta et al, 2016; Musso et al, 2017). In the progression from NAFLD to nonalcoholic steatohepatitis (NASH), these polymorphisms, which are associated with Mer expression, are linked to reduced risk for liver fibrosis (Cavalli et al, 2017). In turn, recent analyses have indicated that mice display reduced levels of a NASH-like fibrosis that is induced by high-fat diet, via reduced activation of hepatic stellate cells by macrophages that are normally Mer+ (Cai et al, 2019). Together, these findings suggest that Mer signaling promotes hepatic fibrosis. Independently, patients with acute liver failure have been found to display markedly elevated numbers of Mer+ macrophages and monocytes in their liver, lymph nodes, and blood circulation (Barcena et al, 2015; Bernsmeier et al, 2015; Triantafyllou et NSC632839 al, 2018), and Mer has, therefore, emerged as a target in the treatment of liver disease (Mukherjee et al, 2016; Bellan et al, 2019). With respect to Axl, elevated serum levels of soluble Axl extracellular domain (sAxl) have been found to be a biomarker for hepatocellular carcinoma (Reichl & Mikulits, 2016), and mice lacking Gas6, the obligate Axl ligand (Lew et al, 2014), display enhanced tissue damage in a liver ischemia model (Llacuna et al, 2010). At the same time, Axl+ monocytes are elevated in patients with cirrhosis (Brenig et al, 2020), and serum Gas6 and sAxl levels are elevated in patients with hepatitis C computer virus and alcoholic liver disease (Barcena et al, 2015). Divergent functions for Axl and Mer have been reported in chronic models of fibrosis, where mice exhibited enhanced NASH development when fed a high-fat diet, whereas mice were guarded (Tutusaus et al, 2019). These multiple findings notwithstanding, the general importance of TAM receptor signaling to both normal liver physiology and to acute, rapid-onset liver insults has not been assessed. We have, therefore, exploited a set of standard and conditional mouse mutants in the and genes and subjected these mutants to established models NSC632839 of both acute liver damage and chronic fibrosis, to make NSC632839 these assessments. Results Expression of TAM receptors in mouse liver We first used immunohistochemistry (IHC) to delineate TAM expression in adult mouse liver. Most prominently, we detected very strong expression of both Axl (Fig 1A) and Mer (Fig 1B) in all KCs. These liver macrophages did not express detectable Tyro3 (data not shown). Most tissue macrophages (e.g., peritoneal macrophages and microglia) express high levels of Mer and low levels of Axl at constant state (Zagrska et al, 2014;.