Decreased ferroportin in hepatocytes promotes macrophages polarize towards an M2-like phenotype and liver fibrosis

Abstract

Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin (FPN1). However, the functions of FPN1 in hepatocyte secretion and macrophage polarization remain unknown. CD68 immunohistochemical staining and double immunofluorescence staining for F4/80 and Ki67 in transgenic mouse livers showed that the number of macrophages in FPN1−/+ and FPN1−/− mouse livers was significantly increased compared to that in WT (FPN+/+) mice. FPN1 downregulation in hepatic cells increased the levels of the M2 markers CD206, TGF- β, VEGF, MMP-9, Laminin, Collagen, IL-4 and IL-10. Furthermore, the expression of CD16/32 and iNOS, as M1 markers, exhibited the opposite trend. Meanwhile, α-SMA immunohistochemistry and Sirius red staining showed that the trend of liver fibrosis in FPN1−/− mice was more significant than that in control mice. Similarly, in vitro FPN1 knockdown in L02-Sh/L02-SCR liver cell lines yielded similar results. Taken together, we demonstrated that downregulated FPN1 expression in hepatocytes can promote the proliferation and polarization of macrophages, leading to hepatic fibrosis. Above all, the FPN1 axis might provide a potential target for hepatic fibrosis.

Injectable Antibacterial Hydrogel with Asiaticoside‐Loaded Liposomes and Ultrafine Silver Nanosilver Particles Promotes Healing of Burn‐Infected Wounds

“…In contrast, macrophages also secrete anti‐inflammatory cytokines, such as transforming growth factor‐ β 1 (TGF‐ β 1) and IL‐4, which are the main modulators of the healing process after tissue injury. [ 54 ] Compared to the control group, the gene expression of TGF‐ β 1 and IL‐4 in the RQLAg group increased ( p < 0.01) (Figure 7D,E). In summary, the inflammatory characterization results show that the RQLAg hydrogel can reduce inflammatory cytokines, increase anti‐inflammatory cytokines at the wound site, and create a more favorable environment for wound repair.…”

Role of ferroptosis in fibrosis: From mechanism to potential therapy

“…[36] In addition, a study reported that FPN deficiency-induced ferroptotic hepatocytes drove macrophage proliferation and M2 polarization by increasing IL-10 and TGF-b release concomitantly with aggravated liver fibrosis. [37] Ferroptotic cells can recruit macrophages by releasing cytokines. Monocyte chemoattractant protein-1 (MCP-1/ CCL2) is a key chemokine signal involved in fibrosis across multiple organs.…”

“…[36] In addition, a study reported that FPN deficiency-induced ferroptotic hepatocytes drove macrophage proliferation and M2 polarization by increasing IL-10 and TGF-β release concomitantly with aggravated liver fibrosis. [37]…”