The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice

Abstract

At present, there are no effective antifibrotic drugs for patients with chronic liver disease; hence, the development of antifibrotic therapies is urgently needed. Here, we performed an experimental and translational study to investigate the potential and underlying mechanism of quercetin treatment in liver fibrosis, mainly focusing on the impact of quercetin on macrophages activation and polarization. BALB/c mice were induced liver fibrosis by carbon tetrachloride (CCl4) for 8 weeks and concomitantly treated with quercetin (50 mg/kg) or vehicle by daily gavage. Liver inflammation, fibrosis, and hepatic stellate cells (HSCs) activation were examined. Moreover, massive macrophages accumulation, M1 macrophages and their related markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1) in livers were analyzed. In vitro, we used Raw 264.7 cells to examine the effect of quercetin on M1-polarized macrophages activation. Our results showed that quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation. These results were attributed to the reductive recruitment of macrophages (F4/80+ and CD68+) into the liver in quercetin-treated fibrotic mice confirmed by immunostaining and expression levels of marker molecules. Importantly, quercetin strongly inhibited M1 polarization and M1-related inflammatory cytokines in fibrotic livers when compared with vehicle-treated mice. In vitro, studies further revealed that quercetin efficiently inhibited macrophages activation and M1 polarization, as well as decreased the mRNA expression of M1 macrophage markers such as TNF-α, IL-1β, IL-6, and nitric oxide synthase 2. Mechanistically, the inhibition of M1 macrophages by quercetin was associated with the decreased levels of Notch1 expression on macrophages both in vivo and in vitro. Taken together, our data indicated that quercetin attenuated CCl4-induced liver inflammation and fibrosis in mice through inhibiting macrophages infiltration and modulating M1 macrophages polarization via targeting Notch1 pathway. Hence, quercetin holds promise as potential therapeutic agent for human fibrotic liver disease.

DrAFC: Drug Repositioning Through Anti-Fibrosis Characteristic

“…In Drugbank experimental drugs, multiple drugs with great repositioning potential (Related Genes>500 and Diseases>20, Figure 3b, Table S3) were developed for fibrotic diseases and other diseases. Quercetin was discovered to ameliorate liver fibrosis through regulating macrophage infiltration and polarization, and it could alleviate IPF through fibroblasts apoptosis[29, 30]. Based on our results, we confirm that quercetin interacts with numerous genes and is strongly linked to multiple diseases (Repositioning score=0.856, Related Genes=3938, Diseases=150, Table S3).…”

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

“…Compelling evidence linked inflammation to the development of liver fibrosis . Currently, few effective drugs can be used to treat liver fibrosis, and suppressing liver inflammation is an effective strategy to control liver fibrosis .…”

“…Compelling evidence linked inflammation to the development of liver fibrosis. 1,2 Currently, few effective drugs can be used to treat liver fibrosis, and suppressing liver inflammation is an effective strategy to control liver fibrosis. 3 It is well known that hepatic stellate cells (HSCs) activation is regarded as a critical step in mediating liver fibrosis, 4 and however, continuous secretion of inflammatory cytokines in liver tissue will lead to the persistent activation of HSCs.…”

Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

“…Culture and Treatment of RAW264.7 Macrophage Cells RAW264.7 murine cells were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences (Shanghai, China) and cultured in undifferentiated RAW macrophages conditioned medium as previously described (38,39). Briefly, the cells cultured in T25 flasks in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), glutamine (2 mM L), penicillin (50 U/mL), and streptomycin (50 µg/mL) at 37 and 5% CO 2 .…”

“…Individual scores were assigned for each parameter. Moreover, liver fibrosis was also evaluating using the NIH ImageJ free software (Bethesda, Maryland, USA) on Masson's trichrome-stained sections in a blinded manner (23,38).…”