Abstract
Macrophages have been recognized as key players in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether pharmacological attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts on NAFLD. We analyzed the pro- and anti-inflammatory gene expression of murine macrophages and human monocytes in vitro in the presence or absence of imatinib. In a time-resolved study, we characterized metabolic disease manifestations such as hepatic steatosis, systemic and adipose tissue inflammation as well as lipid and glucose metabolism in obese mice at one and three months of imatinib treatment. Our results showed that imatinib lowered pro-inflammatory markers in murine macrophages and human monocytes in vitro. In obese mice, imatinib reduced TNFα-gene expression in peritoneal and liver macrophages and systemic lipid levels at one month. This was followed by decreased hepatic steatosis, systemic and adipose tissue inflammation and increased insulin sensitivity after three months. As the transcription factor sterol regulatory element-binding protein (SREBP) links lipid metabolism to the innate immune response, we assessed the gene expression of SREBPs and their target genes, which was indeed downregulated in the liver and partially in peritoneal macrophages. In conclusion, targeting both inflammatory and lipogenic pathways in macrophages and liver as shown by imatinib could represent an attractive novel therapeutic strategy for patients with NAFLD.
Highlights
As a result of the increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide[1]
Imatinib was tested in differentially activated peritoneal macrophages in vitro (M0, M1, M2) after the optimization of housekeeping genes (HKGs), the timing of macrophage activation and the dose of imatinib (Supplementary Fig. S1): In peritoneal M1-activated macrophages, imatinib lowered multiple pro-inflammatory genes, most consistently TNFα
To find out whether imatinib only dampens pro-inflammatory genes or promotes anti-inflammatory gene expression, anti-inflammatory genes were assessed in differentially activated macrophages
Summary
As a result of the increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide[1]. Anti-inflammatory effects upon imatinib treatment include adoption of an anti-inflammatory phenotype in tumor-associated macrophages[23], suppressed glycolysis as an indication for anti-inflammatory polarization in leukemia cells[24], reduced acute liver injury[25], and attenuated adipose tissue inflammation in obese mice[21]. Based on the anti-inflammatory and anti-diabetic effects of imatinib potentially involving PPARγ, the aim of our study was to assess whether imatinib directly attenuates macrophages and could be used in disease states with pathological macrophage activation such as NAFLD. The concept of pharmacological macrophage attenuation in NAFLD is intriguing as restoring pathologically activated macrophages could potentially target the root cause of NAFLD, and other metabolic disease manifestations such as adipose tissue and systemic inflammation and insulin resistance. A more profound understanding of macrophage modulation and the molecular pathways involved holds the promise for new treatment strategies in NAFLD and metabolic disease
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