MIR31HG Modulates IL-4 Secretion by Keratinocytes and M2-Like Macrophage Polarization to Promote Local Immunosuppression in Condyloma Acuminata.

BACKGROUND: Condyloma acuminata (CA) is clinically associated with localized immunosuppression, yet the mechanisms underlying HPV-mediated immune evasion remain poorly understood. Although the long non-coding RNA MIR31HG has been implicated in inflammatory regulation, its role in the immunosuppressive microenvironment of CA has not been explored. METHODS: We analyzed MIR31HG expression in CA and normal skin tissues. HaCaT cells infected with CA-derived HPV6/11 (HPV6/11-HaCaT) and controls treated with skin-derived supernatant were established to explore the association between HPV6/11 and MIR31HG. The HPV6/11-HaCaT model was further used to investigate the effects of MIR31HG on cytokine secretion and macrophage polarization. Bioinformatic prediction, dual-luciferase reporter assays and rescue experiments targeting PI3K/AKT and IL-4 signaling were performed to investigate the underlying molecular mechanisms. RESULTS: MIR31HG was significantly upregulated in CA keratinocytes compared with normal skin. In vitro, HPV6/11 induced the expression of MIR31HG. Functional studies demonstrated that MIR31HG induced a cytokine shift in HPV6/11-HaCaT cells, characterized by elevated anti-inflammatory IL-4 and reduced pro-inflammatory mediators, including TNF-α, IFN-β, IL-6 and IL-8. This IL-4 surge promoted M2-like macrophage polarization, a hallmark of immunosuppression, thereby contributing to an immunosuppressive microenvironment in CA. Mechanistically, MIR31HG functioned as a ceRNA for miR-214-3p in HPV6/11-HaCaT cells, leading to enhanced PTEN expression and subsequent suppression of the PI3K/AKT pathway, thereby contributing to an immunosuppressive cytokine profile and M2-like macrophage polarization. CONCLUSION: Our findings highlight the immunomodulatory role of keratinocytes in CA and highlight the MIR31HG/IL-4 axis as a novel therapeutic target for CA, bridging mechanistic insight with translational potential.