IL‐25 protects against high‐fat diet‐induced hepatic steatosis in mice by inducing IL‐25 and M2a macrophage production

• Published in: Immunology and cell biology 2019-02, Vol.97 (2), p.165-177
• Main Authors: Zheng, Xue‐Lian, Wu, Jian‐Ping, Gong, Yue, Hong, Jun‐Bo, Xiao, Hai‐Ying, Zhong, Jia‐Wei, Xie, Bo, Li, Bi‐Min, Guo, Gui‐Hai, Zhu, Xuan, Wang, An‐Jiang
• Format: Article
• Language: English
• Subjects: Animals; Diet, High-Fat; Fatty liver; Fatty Liver - etiology; Fatty Liver - metabolism; Fatty Liver - prevention & control; Hepatocyte; Hepatocytes; Hepatocytes - metabolism; High fat diet; Interleukin-13 - metabolism; Interleukin-17 - metabolism; Interleukin-17 - pharmacology; interleukin‐25; Liver - metabolism; Liver diseases; macrophage; Macrophage Activation - drug effects; Macrophages; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic fatty liver disease; Recombinant Proteins - pharmacology; Rodents; Signal Transduction - physiology; Stat6 protein; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Steatosis
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12207

Interleukin (IL)‐25 is a cytokine that has previously been shown to have a protective role against nonalcoholic fatty liver disease (NAFLD), which is associated with the induction of M2 macrophage differentiation. However, the direct relationships between IL‐25 expression regulation, M2 induction and NAFLD remain unknown. In this study, we demonstrate that IL‐25 promotes hepatic macrophage differentiation into M2a macrophages both in vivo and in vitro via the IL‐13/STAT6 pathway. M2 macrophages that were differentiated in vitro were able to ameliorate high‐fat diet HFD‐induced hepatic steatosis. Furthermore, we found that IL‐25 treatment, both in vitro and in vivo, promotes direct binding of STAT6 to the IL‐25 gene promoter region. This binding of STAT6 in response to IL‐25 treatment also resulted in the increase of IL‐25 expression in hepatocytes. Together, these findings identify IL‐25 as a protective factor against HFD‐induced hepatic steatosis by inducing an increase of IL‐25 expression in hepatocytes and through promotion of M2a macrophage production. Interleukin‐25 (IL‐25) alternatively activates M2a macrophages in vivo and in in vitro. IL‐25‐induced M2 macrophages can ameliorate high‐fat diet‐induced hepatic steatosis. IL‐25/STAT6/IL‐25 positive feedback loop regulates the expression of endogenous IL‐25 in hepatocytes.