Pathologic role of excessive DNA as a trigger of keratinocyte proliferation in psoriasis

: Psoriasis is characterized by excessive growth and aberrant differentiation of epidermal keratinocytes due to persistent inflammation. However, the underlying mechanism that triggers immune activation in psoriasis is not clear. In this study, we explored excessive DNA as a potential trigger of psoriasis using cultured human keratinocytes and psoriatic skin tissues. We demonstrated that human genomic DNA fragments induced tumor necrosis factor-α (TNF-α) expression, hyperproliferation, and overexpression of heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor α (TGF-α), accompanied by defective expression of keratins 1 and 10 in cultured normal human epidermal keratinocytes, which have a similar phenotype as that of keratinocytes in psoriatic skin lesions. In psoriatic lesions, we found high levels of double-stranded (ds)DNA fragments, accompanying keratinocytes expressing Ki-67, HB-EGF and TNF-α. In addition, we showed that 1,25-dihydroxyvitamin D3 inhibited genomic DNA fragment-induced TNFA and interleukin-1β (IFNB) expression in human keratinocytes, and intact function of cathelicidin antimicrobial peptide was required for this effect. These results suggest that excessive dsDNA fragments likely act as a risk factor for immune activation in psoriasis, and the active form of vitamin D can prevent genomic DNA-mediated skin inflammation via cathelicidin antimicrobial peptide.