RegIIIγ promotes the proliferation, and inhibits inflammation response of macrophages by Akt, STAT3 and NF-κB pathways

As an inflammatory regulator, intestinal regenerating islet-derived 3 gamma (RegIII gamma) contributes to alleviating liver injury in liver diseases and colitis. However, it is unclear whether hepatic RegIII gamma exerts a vital impact on liver regeneration (LR). In this study, the expression profile and localization of RegIII gamma in LR were demonstrated by microarray analysis, qRT-PCR and immunofluorescence staining. Then, RAW264.7 cells with RegIII gamma deficiency and overexpression were obtained by the CRISPR/Cas9 system and lentivirus infection, respectively. MTT, flow cytometry, EdU, transwell, neutral red phagocytosis, and NO assays were performed to detect the functions of RegIII gamma in RAW264.7 cell proliferation and inflammation. Finally, the regulatory mechanism of RegIII gamma was explored by co-immunoprecipitation and Western blot assays. According to our findings, RegIII gamma showed significant expression changes in Kupffer cells during LR, and RegIII gamma overexpression stimulated the viability, proliferation, phagocytosis and migration of RAW264.7 cells, whereas RegIII gamma deficiency reversed these effects. Similarly, RegIII gamma overexpression facilitated the expression of HO-1 and IL-10, while RegIII gamma deficiency promoted NO production and p-Akt, p-STAT3, p-p65 and TNF-alpha expression. In conclusion, RegIII gamma may facilitate LR by promoting the proliferation of macrophages and inhibiting their inflammatory response through Akt, STAT3 and NF-kappa B pathways in the priming stage of LR.