Inhibition of KPNA2 by ivermectin reduces E2F1 nuclear translocation to attenuate keratinocyte proliferation and ameliorate psoriasis-like lesions

Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113360. doi: 10.1016/j.intimp.2024.113360. Epub 2024 Oct 10.

Abstract

Psoriasis is a chronic, immune-mediated skin disease with a significant global prevalence. Karyopherin subunit alpha 2 (KPNA2), a nuclear transport protein involved in cellular activities such as differentiation, proliferation, apoptosis, and immune response, has emerged as a potential biomarker in several diseases. Our study found that KPNA2 was significantly upregulated in psoriasis patients and in imiquimod (IMQ)-induced psoriasis mouse models by bioinformatics and molecular biotechnology. In vivo, treatment with ivermectin, a KPNA2 inhibitor, significantly improved psoriasis symptoms in mice as evidenced by reduced erythema, desquamation, and skin thickness. Histopathological staining revealed decreased expression of KPNA2, K17, and Ki67 in ivermectin-treated mice, suggesting reduced abnormal differentiation and proliferation of keratinocytes. Transcriptome data and immunoblotting analysis showed that KPNA2 inhibition reduced inflammation and keratinocyte proliferation and differentiation in IMQ-induced mice. In vitro, EdU (5-ethynyl-2'-deoxyuridine) and flow cytometry experiments demonstrated that the downregulation of KPNA2 expression in HaCaT cells was capable of inhibiting the EGF (Epidermal Growth Factor)-induced activation of AKT/STAT3 signaling and keratinocytes proliferation. In addition, nuclear-cytoplasmic protein separation and immunofluorescence localization experiments showed that KPNA2 inhibition affected the nuclear translocation of E2F transcription factor 1 (E2F1), a process critical for keratinocyte proliferation. This study elucidated the role of KPNA2 in the pathogenesis of psoriasis and highlighted its potential as a target for future psoriasis therapies. These findings provide new insights into targeted therapy for psoriasis and have significant implications for future clinical treatment.

Keywords: Chronic inflammation; KPNA2 regulation; Nuclear-cytoplasmic transport; Psoriasis.

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation* / drug effects
  • Disease Models, Animal
  • E2F1 Transcription Factor* / genetics
  • E2F1 Transcription Factor* / metabolism
  • Female
  • HaCaT Cells
  • Humans
  • Imiquimod
  • Ivermectin* / pharmacology
  • Ivermectin* / therapeutic use
  • Keratinocytes* / drug effects
  • Keratinocytes* / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Psoriasis* / drug therapy
  • Signal Transduction / drug effects
  • Skin / drug effects
  • Skin / pathology
  • alpha Karyopherins* / metabolism

Substances

  • alpha Karyopherins
  • Ivermectin
  • E2F1 Transcription Factor
  • Imiquimod
  • KPNA2 protein, human
  • E2F1 protein, human
  • karyopherin alpha 2