FGF21 alleviates chronic inflammatory injury in the aging process through modulating polarization of macrophages.

Previous studies reported that FGF21 prolongs life span and delays the body senescence, but the mechanism is not clear. The present study was designed to investigate the effects of FGF21 on hepatic senescence in aging mice and further research the mechanism. The 14-month-old male mice were administered with PBS, FGF21 or metformin once daily for 6 months. Results showed that FGF21 alleviated liver injury and inhibited accumulation of senescence markers SASP, P53 and P16 in the livers of aging mice. Subsequently we found that the aging mice treated by FGF21 showed transition of type 1 macrophages (M1) to type 2 macrophages (M2) in the livers. Next, we used THP-1 macrophages triggered by LPS to study effects of FGF21 on macrophages. Macrophages triggered by LPS exhibited features of M1, but the addition of FGF21 decreased the expression of M1 markers, and promoted the macrophages to exhibit features of M2. Results showed that the effects of FGF21 on macrophages were associated with the AMPK pathway. After adding AMPK inhibitor, the effects of FGF21 were inhibited, which was associated with the NF-κB signaling pathway. Finally, co-culturing differentiated macrophages and hepatocytes, we found that the large amount of pro-inflammatory factors such as IL-6 promoted hepatocyte senescence, which exhibited enhanced P53, P16 and β-galactosidase. This was contrary to hepatocytes co-cultured with macrophages treated by FGF21. These results indicate that FGF21 alleviates hepatic senescence injury by modulating the polarization of macrophages through the AMPK /NF-κB signaling pathway.