Corrigendum: TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation.

[This corrects the article DOI: 10.3389/fphar.2020.00010.].

TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation.

Tumor necrosis factor (TNF)-α-stimulated protein 6 (TSG-6) is a secreted protein with diverse tissue protective and anti-inflammatory properties. We aimed to investigate its effective in treating mice with alcoholic hepatitis (AH) and the associated mechanisms. AH was induced in 8-10 week female C57BL/6N mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) injection of recombinant mouse TSG-6 or saline were performed in mice on day 10. Blood samples and hepatic tissues were collected on day 11. Biochemistry, liver histology, flow cytometry, and cytokine measurements were conducted. Compared to the normal control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic macrophage infiltration, serum and hepatic interleukin (IL)-6, and tumor necrosis factor (TNF)-α, which were markedly reduced by i.p. injection of rmTSG-6. Compared to the normal control mice, the hepatic glutathione (GSH), accumulation of M2 macrophages, serum, and hepatic IL-10 and TSG-6 were prominently reduced in the AH mice, which were significantly enhanced after i.p. injection of rmTSG-6. Compared to the normal control mice, hepatic activation of signal transducer and activator of transcription 3 (STAT3) was significantly induced, which was markedly suppressed by rmTSG-6 treatment. TSG-6 were effective for the treatment of AH mice, which might be associated with its ability in inhibiting hepatic oxidative stress and inducing hepatic M2 macrophages polarization via suppressing STAT3 activation.

Mesenchymal stem cells reduce alcoholic hepatitis in mice via suppression of hepatic neutrophil and macrophage infiltration, and of oxidative stress.

Mesenchymal stem cells (MSCs) are a population of pluripotent cells that have been tested for the treatment of many inflammatory diseases. It remains unclear whether MSCs were effective in treating mice with alcoholic hepatitis (AH) and its underlying mechanism. In the present study, MSCs were isolated from bone marrow of 4-6 week-old C57BL/6N male mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) transplantation of MSCs or saline were performed in mice on day 10. Blood samples and hepatic tissues were harvested on day 11. Biochemical, liver histological and flow cytometric analyses were performed. Compared to the control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic neutrophil and macrophage infiltration (P<0.001), which were markedly reduced by i.p. transplantation of MSCs (P<0.01). Compared to the control mice, the hepatic glutathione (GSH) was prominently lower in the AH mice (P<0.001), which was markedly enhanced after i.p. injection of MSCs (P<0.001). MSCs were effective for the treatment of AH mice, which might be associated with their ability in inhibiting hepatic neutrophil and macrophage infiltration, and alleviating oxidative stress.

Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation.

BACKGROUND: Mesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear. METHODS: MSCs were isolated from the bone marrow (BM) of 4-6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed. RESULTS: MSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone. CONCLUSIONS: BM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.