HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3-miR124 Axis.

Bal Krishna Chand Thakuri,Xiao Y Wu,Lam N T Nguyen,Mohamed El Gazzar,Lam N Nguyen,Juan Zhao,Shunbin Ning,Zeyuan Lu,Ling Wang,Yong Jiang,Xindi Dang,Zhi Q Yao,Sushant Khanal,Jinyu Zhang,Jonathan P Moorman,Madison Schank,Dechao Cao

doi:10.3390/cells9122715

Abstract

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR–RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR–RUNX1–STAT3–miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.

Highlights

Hepatitis C virus (HCV) can employ different strategies to evade host immunity and harness virus persistence, serving as an excellent model for studying the mechanisms of virus-mediated host immune dysfunction and viral persistence in humans [1,2]
Human Myeloid-derived suppressor cells (MDSCs) are immature myeloid cell phenotyped as CD33+ HLA-DR−/low, which can be further categorized into monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs) based on the level of expression of the monocytic marker CD14 [40,41]
We found that the frequencies of total MDSCs (CD33+ HLA-DR−/low ), M-MDSCs (CD33+ HLA-DR−/low CD14+ ), and G-MDSCs (CD33+ HLA-DR−/low CD14− ) were significantly increased in Peripheral blood mononuclear cells (PBMCs) in individuals with chronic hepatitis C virus (HCV) infection (Figure 1A–C)

Summary

Introduction

Hepatitis C virus (HCV) can employ different strategies to evade host immunity and harness virus persistence, serving as an excellent model for studying the mechanisms of virus-mediated host immune dysfunction and viral persistence in humans [1,2]. “virological cure” does not always lead to “immunological cure”, and some immune disorders persist after DAA treatment with sustained virological response (SVR) [5]. The failure to manage many chronic infectious diseases, including HCV, stems from our incomplete understanding of the pathogen–host interactions that can dysregulate host immune responses. MDSCs contribute to immune homeostasis via limiting excessive inflammatory processes, but their expansion may be at the expense of pathogen elimination, resulting in persistent infection [8]. We and others reported that MDSCs expand and inhibit T cell functions in multiple disease models, including chronic viral (HCV and HIV) infections [11,12,13,14,15,16,17,18]

Methods

Results

Conclusion