PRMT5 promotes psoriatic inflammation through mediating dimethylation of p65 in keratinocytes

Psoriasis is a chronic inflammatory skin disease driven by aberrant keratinocyte activation and immune dysregulation. Protein arginine methyltransferase 5 (PRMT5) was identified as a candidate regulator in psoriatic keratinocytes, yet its function and mechanistic role in psoriasis pathogenesis remain unclear.

We analyzed multiple public bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) transcriptomic datasets from psoriasis patients to assess PRMT5 mRNA expression and distribution. Protein expression was further validated by immunofluorescence staining of psoriatic lesion biopsies. Functional validation employed siRNA-mediated Prmt5 knockdown in imiquimod-induced psoriasis model. Transcriptomic profiling combined with in vitro human primary keratinocytes experiments was performed with PRMT5 knockdown or inhibition to map downstream potential mechanisms. Specific mechanistic investigations included co-immunoprecipitation, molecular docking, GST pull-down, mass spectrometry, and site-directed mutagenesis to characterize the PRMT5-p65 interaction and symmetric dimethylarginine (SDMA) modification. Finally, the therapeutic potential of PRMT5 inhibition by EPZ015666 was evaluated in imiquimod and IL-23-induced psoriasis models.

PRMT5 was markedly upregulated in psoriatic keratinocytes. Knockdown of Prmt5 reduces local inflammation responses in the imiquimod-induced mouse model. Transcriptomic profiling combined with in vitro detection defined that inhibition of PRMT5 can dampen the inflammatory response of keratinocytes. Mechanistically, PRMT5 inhibition markedly reduces p65 protein levels, prompting further exploration of the PRMT5-p65 axis. Co-immunoprecipitation, molecular docking and GST pull down assay confirmed a direct PRMT5-p65 interaction; PRMT5 knockdown attenuated this interaction, diminishes symmetric dimethylarginine (SDMA) modification of p65, and compromises p65 protein stability. Accordingly, p65 overexpression restored inflammatory cytokine production in PRMT5-knockdown keratinocytes, functionally validating this regulatory axis. Mass spectrometry combined with site-directed mutation experiments revealed that PRMT5 facilitates p65 symmetric dimethylation at R158 and R166, which suppresses autophagy-mediated lysosomal degradation, thereby promoting p65-dependent cytokines expression. Pharmacological inhibition of PRMT5 with EPZ015666 ameliorates psoriatic inflammatory responses in vivo, underscoring its translational potential value.

These findings establish a PRMT5-p65 regulatory axis wherein PRMT5-mediated symmetric dimethylation at R158 and R166 stabilizes p65 by autophagy-mediated lysosomal degradation and amplifies NF-κB-driven inflammation in keratinocytes, identifying PRMT5 as a potential therapeutic target in psoriasis.