IL-25 or IL-17E Protects against High-Fat Diet–Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6

Abstract

Interleukin-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet proteins were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased lipid droplet proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively-activated Kupffer cells/macrophages, and decreased expression of lipid droplet proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in down-regulation of lipid droplet proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, while exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.

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

“…Furthermore, our results confirm that mice treated with IL‐25 after a HFD exhibited a polarized type‐2 immunity which is characterized by IL‐13 upregulation, promoting the development of M2 macrophages in the liver (Figure c, g) . The M2 macrophage markers, arginase I (Arg1), chitinase‐3‐like 3 (Chi3 l3 or YM‐1) and inflammatory zone 1 (FIZZ1 or Retnla), were also shown to be upregulated in IL‐25‐treated, HFD‐fed mouse livers (Figure d, g), a finding consistent with our previous studies . Moreover, CCL17, CCL22 and CCL24 expression levels were significantly upregulated (Figure e, g), while CCL1, CXCL13, CCL16 and CCL18 expression levels remained unchanged (Figure f, g).…”

“…Given these results, the direct application of IL‐25 in NAFLD should be approached with caution. Previous work from our laboratory demonstrates that IL‐25‐treated mice exhibit a polarized type 2 immunity characterized by an upregulation of IL‐13, leading to the development of M2 macrophages in the liver . We also found that adoptively transferred macrophages could inhibit liver and adipose tissue M1 macrophages, but this transfer does not have a direct effect on the adipose tissue or the insulin signaling (Supplementary figures 4e and 7a–e).…”

“…M2 macrophages; on the other hand, have been demonstrated to selectively promote M1 macrophage apoptosis through the release of IL‐10, and thus play a role in anti‐inflammatory processes and healthy liver maintenance . Our previous studies demonstrated that IL‐25‐treated mice exhibited a polarized type‐2 immunity that was characterized by an upregulation of IL‐13, leading to the development of M2 macrophages in vivo . However, the direct role of IL‐25 on macrophage induction remains unclear.…”

“…Recently, the direct administration of IL‐25 has been considered in the treatment of breast cancer, colon cancer and NAFLD . However, exogenous high IL‐25 levels have been demonstrated to induce Th2‐type immune responses, indicating that it could possibly contribute to the pathogenesis of numerous disease states .…”

“…We previously demonstrated that IL‐25 provides a protective effect against high‐fat diet HFD‐induced NAFLD. This protective effect of IL‐25 is associated with the upregulation of IL‐13, activation of the JAK–STAT6 pathway and induction of M2 macrophage differentiation . It is hypothesized that the beneficial effects observed with IL‐25 are derived from its ability to induce M2 macrophage differentiation.…”