Characterization of Liver Monocytic Myeloid-Derived Suppressor Cells and Their Role in a Murine Model of Non-Alcoholic Fatty Liver Disease

Abstract

Myeloid-derived suppressor cells (MDSCs) are potent suppressors of T cell immunity in tumors and inflammatory diseases. They are identified by surface expression of CD11b+Gr1+ in mice, and CD11b+Gr1+ cells accumulate in the livers of obese mice. However, many myeloid cells share these CD11b+Gr1+ markers. Accordingly, the aim of this study was to identify the authentic phenotype of MDSCs and investigate their functions in non-alcoholic fatty liver disease (NAFLD). C57BL/6J mice were divided into 2 diet groups: a normal control group and high-fat group to induce NAFLD. We demonstrated that monocytic CD11b+Gr1dim cells could be further divided into 2 populations based on side scatter (SSC) during flow cytometry. We found that SSClowCD11b+Gr1dim cells accumulated in the livers of NAFLD mice over time, and that these cells were recruited by the chemokine CCL2 and its receptor CCR2 and might expand in the liver via macrophage colony-stimulating factor stimulation. Furthermore, SSClowCD11b+Gr1dim cells had a strong suppressive ability on T cells; this effect was not observed for SSChighCD11b+Gr1dim cells, and was dependent on nitric oxide production by inducible nitric oxide synthase. Our findings demonstrate that SSClowCD11b+Gr1dim cells represent authentic MDSCs in NAFLD livers, and might serve an important negative feedback function in liver inflammation.

Granulocytic myeloid‐derived suppressor cell population increases with the severity of alcoholic liver disease

“…13 There are significantly more mMDSCs in the liver in patients with non-alcoholic fatty liver disease than in HCs. 27 Taken together, the data indicate that gMDSCs are increased in ALD patients and associated with disease progression.…”

CD11b+Gr‐1dim Tolerogenic Dendritic Cell–Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice

“…These cells are distinct from the CD11b+Gr‐1 dim tolerogenic DC–like cells in our study, which are not MDSCs and express low levels of F4/80 but high levels of CD11c. Recently, another group described SSC low CD11b+Gr‐1 dim cells with immunosuppressive function via a nitric oxide–dependent mechanism in the liver of obese mice . These SSC low CD11b+Gr‐1 dim cells are Ly‐6C high Ly‐6G–, express CD80 and PDL‐1 but not CD11c, and are recognized as a subset of monocytic MDSCs.…”

The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process

“…Three chemokines, i.e. CCL2 (MCP-1, monocyte chemoattractant protein-1), CXCL2 (MIP-2, macrophage inflammatory protein-2), and CXCL8 (IL-8), are the most important chemokines directing the chemotaxis of MDSCs (Huang et al, 2007;Katoh et al, 2013;Alfaro et al, 2016;Yao et al, 2016). These chemokines are also included in the secretome of senescent cells (Section 5.1.).…”

“…There is convincing evidence that MDSCs and Tregs accumulate in tissues in many chronic inflammatory conditions, such as chronic infections (Dorhoi and Du Plessis, 2018) as well as in many age-related inflammatory disorders, e.g. hepatic steatosis (Yao et al, 2016) and obesity-linked inflammation in adipose tissues (Okwan-Duodu et al, 2013).…”