Α-Hederin alleviates psoriasiform skin inflammation by inhibiting NF-κB p65/CXCL2 Axis

Background: Psoriasis is a chronic, inflammatory and systemic skin disease. Currently, none of the treatment can effectively prevent the recurrent of psoriasis. α-Hederin is the main active ingredient of the traditional Chineses medicine Ivy, which has been proven to have anti-inflammatory effects. However, its effects on psoriasis and mechanisms of action remain unclear.

Objective: This study aimed to investigate the effects of α-Hederin on murine psoriasis and its underlying mechanisms.

Methods: This study firstly evaluated the therapeutic effects of α-Hederin on psoriasis using imiquimod-induced psoriatic mice. H&E and Ki67 immunohistochemical stainings were used to observe the pathological changes and proliferation of the skin lesions. The expression of inflammatory cytokines in skin lesions was analyzed by ELISA. Subsequently, the network pharmacology was employed to predict the molecular targets of α-Hederin in psoriasis. CXCL2 expression and neutrophil infiltration in skin lesions were evaluated via immunohistochemical staining, immunofluorescent staining and flow cytometry. Finally, the effects of α-Hederin on NF-κB p65 pathway were evaluated. The binding of α-Hederin to NF-κB p65 protein was verified through molecular docking, molecular dynamics simulation, CETSA and DARTS.

Results: α-Hederin significantly improved IMQ-induced psoriasiform skin lesions and inflammation in mice. It also reduced the expression of CXCL2 and infiltration of CD11b⁺Ly6G⁺ neutrophils in the skin of psoriatic mice. Importantly, administration of recombinant CXCL2 protein aggravated the skin lesions and increased CD11b⁺Ly6G⁺ neutrophil infiltration in psoriatic mice previously treated with α-Hederin. Furthermore, α-Hederin inhibited the production of CXCL2 in HaCaT cells and migration of neutrophils to HaCaT cells. But these effects were completely reversed by the CU-T12-9, an NF-κB p65 agonist. Similarly, α-Hederin failed to further alleviate psoriasiform skin lesions and inflammation in mice treated with SC75741 (NF-κB p65 inhibitor). Finally, based on molecular docking, molecular dynamics simulation, CETSA and DARTS, NF-κB p65 was revealed as the direct target of α-Hederin in treating psoriasis.

Conclusion: This study has provided the first evidence that α-Hederin may be a promising anti-psoriatic drug by inhibiting NF-κB p65/CXCL2 axis.

CXCL2; NF-κB p65; Neutrophil; Psoriasis; Α-Hederin.