Iron-accumulating splenocytes may exacerbate non-alcoholic steatohepatitis through the production of proinflammatory cytokines and reactive oxygen species

Non-alcoholic steatohepatitis (NASH) results from non-alcoholic fatty liver disease (NAFLD) via multiple-parallel events, including hepatic triglyceride accumulation, oxidative stress, and inflammation. The complex interaction between the liver and multiple other organs is involved in NASH development. Although spleen-derived humoral factors can directly contribute to NAFLD/NASH onset via the portal vein, the status of the spleen in the early stage of NASH remains unknown. Here, our aim was to investigate whether splenocytes may exacerbate NASH via the generations of reactive oxygen species (ROS) and proinflammatory cytokines. Iron accumulation was observed in the spleen but not the liver, and the proportion of phagocytic macrophages increased in the spleen of Tsumura Suzuki Obese Diabetes (TSOD) mice showing histological characteristics of NASH in the early stage. The splenocytes generated moderate amounts of ROS and released high amounts of tumor necrosis factor (TNF)-α in response to lipopolysaccharide, indicating excessive inflammatory cytokine released by activated macrophages in iron-accumulating spleens. Our results suggest that iron-accumulating splenocytes can easily induce inflammation and contribute to exacerbate NASH via the portal vein. Thus, the regulation of iron metabolism in the spleen should be considered in the development of novel therapeutic targets against NASH.