PMID- 33353065 OWN - NLM STAT- MEDLINE DCOM- 20210709 LR - 20210709 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 9 IP - 12 DP - 2020 Dec 18 TI - HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3-miR124 Axis. LID - 10.3390/cells9122715 [doi] LID - 2715 AB - 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. FAU - Thakuri, Bal Krishna Chand AU - Thakuri BKC AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Zhang, Jinyu AU - Zhang J AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Zhao, Juan AU - Zhao J AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Nguyen, Lam N AU - Nguyen LN AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Nguyen, Lam N T AU - Nguyen LNT AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Schank, Madison AU - Schank M AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Khanal, Sushant AU - Khanal S AUID- ORCID: 0000-0001-8028-6034 AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Dang, Xindi AU - Dang X AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Cao, Dechao AU - Cao D AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Lu, Zeyuan AU - Lu Z AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Wu, Xiao Y AU - Wu XY AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Jiang, Yong AU - Jiang Y AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. FAU - El Gazzar, Mohamed AU - El Gazzar M AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. FAU - Ning, Shunbin AU - Ning S AUID- ORCID: 0000-0001-5484-5779 AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Wang, Ling AU - Wang L AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. FAU - Moorman, Jonathan P AU - Moorman JP AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. AD - Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA. FAU - Yao, Zhi Q AU - Yao ZQ AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. AD - Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA. AD - Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA. LA - eng GR - R01 AI114748/AI/NIAID NIH HHS/United States GR - R21 AI138598/AI/NIAID NIH HHS/United States GR - S10 OD021572/OD/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20201218 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (CD33 protein, human) RN - 0 (Core Binding Factor Alpha 2 Subunit) RN - 0 (Immunosuppressive Agents) RN - 0 (MIRN124 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (RNA, Long Noncoding) RN - 0 (RUNX1 protein, human) RN - 0 (Reactive Oxygen Species) RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) RN - 0 (Sialic Acid Binding Ig-like Lectin 3) RN - 82115-62-6 (Interferon-gamma) RN - EC 3.5.3.1 (Arginase) SB - IM MH - Adult MH - Aged MH - Arginase/metabolism MH - CD4-Positive T-Lymphocytes/cytology MH - Cell Differentiation MH - Cell Proliferation MH - Core Binding Factor Alpha 2 Subunit/*metabolism MH - Exosomes/*virology MH - Female MH - Gene Expression Regulation, Viral MH - Genotype MH - *Hepacivirus MH - Hepatitis C, Chronic/metabolism/virology MH - Humans MH - Immunosuppressive Agents MH - Interferon-gamma/metabolism MH - Male MH - MicroRNAs/*metabolism MH - Middle Aged MH - Myeloid-Derived Suppressor Cells/*cytology/metabolism MH - *RNA, Long Noncoding MH - Reactive Oxygen Species/metabolism MH - STAT3 Transcription Factor/*metabolism MH - Sialic Acid Binding Ig-like Lectin 3/metabolism MH - Up-Regulation MH - Viral Load PMC - PMC7766103 OTO - NOTNLM OT - HCV OT - MDSCs OT - RUNX1 OT - RUNXOR OT - immune suppression OT - miR124 COIS- The authors have no conflict of interest to declare. EDAT- 2020/12/24 06:00 MHDA- 2021/07/10 06:00 PMCR- 2020/12/18 CRDT- 2020/12/23 01:02 PHST- 2020/11/17 00:00 [received] PHST- 2020/12/09 00:00 [revised] PHST- 2020/12/17 00:00 [accepted] PHST- 2020/12/23 01:02 [entrez] PHST- 2020/12/24 06:00 [pubmed] PHST- 2021/07/10 06:00 [medline] PHST- 2020/12/18 00:00 [pmc-release] AID - cells9122715 [pii] AID - cells-09-02715 [pii] AID - 10.3390/cells9122715 [doi] PST - epublish SO - Cells. 2020 Dec 18;9(12):2715. doi: 10.3390/cells9122715.