Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

Abstract

Summary Myeloid‐derived suppressor cells (MDSCs) have been described as suppressors of T‐cell function in many malignancies. Impaired T‐cell responses have been observed in patients with chronic hepatitis C virus infection (CHC), which is reportedly associated with the establishment of persistent HCV infection. Therefore, we hypothesized that MDSCs also play a role in chronic HCV infection. MDSCs in the peripheral blood of 206 patients with CHC and 20 healthy donors were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) of healthy donors cultured with hepatitis C virus core protein (HCVc) were stimulated with or without interleukin 10 (IL‐10). Compared to healthy donors and certain CHC patients with sustained viral response (SVR), CHC patients without SVR presented with a dramatic elevation of G‐MDSCs with the HLA‐DR−/lowCD33+CD14−CD11b+ phenotype in peripheral blood. The frequency of G‐MDSCs in CHC patients was positively correlated with serum HCVc, and G‐MDSCs were induced from healthy PBMCs by adding exogenous HCVc. Furthermore, we revealed a potential mechanism by which HCVc mediates G‐MDSC polarization; activation of ERK1/2 resulting in IL‐10 production and IL‐10‐activated STAT3 signalling. Finally, we confirmed that HCVc‐induced G‐MDSCs suppress the proliferation and production of IFN‐γ in autologous T‐cells. We also found that the frequency of G‐MDSCs in serum was associated with CHC prognosis. HCVc maintains immunosuppression by promoting IL‐10/STAT3‐dependent differentiation of G‐MDSCs from PBMCs, resulting in the impaired functioning of T‐cells. G‐MDSCs may thus be a promising biomarker for predicting prognosis of CHC patients.

Neutrophil Diversity in Health and Disease

“…The latter two types are usually defined as 'suppressive neutrophils' and, unlike LDNs/PMN-MDSCs that often contain immature elements [54,57,66], they are homogeneously composed of populations of mature activated cells [8,54] (Figure 2 and Box 1). Typical LDNs/PMN-MDSCs are observed in septic patients, as well as in those with fungal (e.g., Aspergillus fumigatus and C. albicans) and viral (e.g., bunyavirus and hepatitis C and B virus) infections [54,[67][68][69][70]; they have been shown to inhibit proliferation and interferon γ (IFN-γ) production by CD4 + and CD8 + T cells in vitro via ROS or arginase 1 (ARG1) production [54,[67][68][69][70]. However, their phenotype and functions are less well characterized than those of LDNs/PMN-MDSCs in pregnancy and cancer.…”

Exercise Training Protects Against Heart Failure Via Expansion of Myeloid-Derived Suppressor Cells Through Regulating IL-10/STAT3/S100A9 Pathway

“…The proinflammatory cytokine IL-6 and immunosuppressive cytokine IL-10 play a major role in cardiac hypertrophy and were implicated in the generation and activation of Gr1 + CD11b + MDSCs under different inflammatory conditions. 19,20 Thus, the expression of IL-6 and IL-10 in plasma and heart were measured in different time points (Figure 5A). As shown in Figure 5B and 5C, the levels of IL-6 increased rapidly in isoproterenol-treated mice on day 1 and last for 1 week after cardiac hypotrophy onset.…”

Myeloid-Derived Suppressor Cells: The Expanding World of Helminth Modulation of the Immune System

“…MDSC frequencies have also been observed to increase in other chronic viral infections, including infections with hepatitis C virus (HCV) and hepatitis B virus (HBV). Studies in humans as well as mice provide evidence of expansion of M-MDSC and PMN-MDSC (35,(38)(39)(40)(41). However, the findings indicate the sub-population of MDSC that predominates varies depending on the host and whether the infection is due to HCV or HBV.…”