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.