Protective Effects of MitoTEMPO on Nonalcoholic Fatty Liver Disease via Regulating Myeloid-Derived Suppressor Cells and Inflammation in Mice

Abstract

MitoTEMPO, a mitochondrial antioxidant, has protective effects on liver-related diseases. However, the role of MitoTEMPO on nonalcoholic fatty liver disease (NAFLD) and its possible mechanisms are largely unknown. Here, we investigated the effects of MitoTEMPO on NAFLD using high fat diet- (HFD-) induced obese mice as animal models. MitoTEMPO was intraperitoneally injected into HFD mice. Liver morphological changes were observed by H&E and Oil Red O staining, and the frequency of MDSCs in peripheral blood was analyzed by flow cytometry. Moreover, real-time quantitative PCR, western blot, and immunohistochemistry were conducted to detect the mRNA and protein expressions in the liver tissues. The results showed that the hepatic steatosis in liver tissues of HFD mice injected with MitoTEMPO was significantly ameliorated. Additionally, MitoTEMPO reduced the frequency of CD11b+Gr-1+ MDSCs in peripheral circulation and decreased Gr-1+ cell accumulation in the livers. Further studies demonstrated that MitoTEMPO administration suppressed the mRNA and protein expressions of MDSC-associated proinflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9). Our results suggest that MitoTEMPO appears to be a potential chemical compound affecting certain immune cells and further ameliorates inflammation in obese-associated NAFLD.

Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling

“…These lines of evidence are supported by meta-analysis showing that vitamin E supplementation improves major disease parameters in NAFLD patients, endorsing the oxidative stress concept in fatty liver disease [380]. The synthetic ROS scavenger mito-TEMPO prevented NAFLD associated liver inflammation and steatosis [381] and the related compound mitoQ will most likely show similar beneficial effects [382]. The natural antioxidant flavonoid silibinin improved adverse effects of NASH on the liver and heart in a mouse model (methionine/choline-deficient diet) [383].…”

Dendritic Cells and Myeloid Derived Suppressor Cells Fully Responsive to Stimulation via Toll-Like Receptor 4 Are Rapidly Induced from Bone-Marrow Cells by Granulocyte-Macrophage Colony-Stimulating Factor

“…Their phenotype and functions have been studied in detail only more recently [31,32]. Whilst some studies use CD11b+, GR-1+ phenotype to describe MDSCs in different disease models [33][34][35], others define granulocytic MDSCs as Ly6Ghi and monocytic MDSCs as Ly6Chi [36,37]. Here it is shown that GR-1 hi MDSCs are morphologically granulocytic, confirmed by their expression of Ly6G, and GR-1 int MDSCs are monocytic like cells morphologically and express high levels of Ly6C.…”

The Relationship between Hepatic Myeloid-Derived Suppressor Cells and Clinicopathological Parameters in Patients with Chronic Liver Disease

“…As one of the important compo-nents of the immunosuppressive network, MDSCs have been shown to facilitate tumor formation by blocking the host immune system [6]. Recent studies support the role of MDSCs as essential regulators of chronic inflammatory liver diseases, and MDSCs are expanded in pathological conditions such as malignancy or infection and suppress antitumor immunity [10], and the liver is an important site of MDSC induction for extrahepatic infections and cancer [20][21][22]. The expression of CD33 and CD11b on activated monocytes and macrophages was associated with the disease progression and poor survival of patients [23].…”