LncRNA HOTAIRM1 promotes the immunosuppressive functions of MDSCs through upregulating HOXA1 expression during chronic HCV infection

Abstract

Abstract HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that is critical for the myeloid cell development by targeting HOXA1. We have previously shown that myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that have immunosuppressive functions. However, the role and mechanisms of HOTAIRM1 in the differentiation and function of MDSCs in the setting of viral infection remain elusive. In this study, we demonstrated that HOTAIRM1 and its target gene HOXA1 were upregulated and closely associated with the expression of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and signal transducer and activator of transcription 3 (STAT3) in myeloid cells derived from individuals with chronic hepatitis C virus (HCV) infection. We further revealed that HCV-associated exosomes could induce HATAIRM1 and HOXA1 expression via the miRNA-mediated signaling pathway. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy myeloid cells promoted MDSC differentiation and suppressive functions, evidenced by an increased frequency of MDSCs, expression of immunosuppressive molecules, and inhibition of co-cultured CD4 T cells to produce IFN-γ. Conversely, silencing HOTAIRM1 or HOXA1 expression in HCV myeloid cells partially restored the frequencies of MDSCs, the expressions of their suppressive molecule, and the IFN-γ production in co-cultured T cells. Taken together, this study reveals that HOTAIRM1-HOXA1 enhances the immunosuppressive function of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.