LB964 TET2 participates in the dysregulation of skin barrier in psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease. Dysregulation of the epidermal barrier in psoriasis has been demonstrated and epigenetic modifications have been found to be associated with psoriasis. TET2 has dioxygenase activity and oxidizes 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and is a key regulator of DNA demethylation. There is a lack of studies on the effect of TET2 on the epidermal barrier in psoriasis. We observed reduced expression of TET2 and 5hmc in the lesions of psoriasis patients. In imiquimod psoriatic dermatitis mice, we obtained similar results by immunohistochemistry. We constructed epidermal TET2 conditional knockout mice (TET2CKO). In the imiquimod psoriasis dermatitis model, TET2CKO mice presented more severe erythema, scaling and skin thickness. The TEWL assay was performed on imiquimod-treated mice and was elevated in the TET2CKO group. This indicates that epidermal TET2 deficiency exacerbates psoriatic dermatitis in mice. We next examined the expression of K14, K10, filaggrin, involucrin, which represent proliferation and differentiation, TET2CKO mice showed K14, involucrin increased and K10, filaggrin decreased. TET2 absence may accelerate the proliferation and inhibit differentiation of keratinocytes. We subsequently observed that intercellular linker molecules Claudin-1 and E-cadherin were both downregulated in TET2CKO mice. In conclusion, deletion of epidermal TET2 is involved in dysregulation of the skin barrier. By RNAseq, we found that FLG mRNA is reduced after TET2 knockdown. Deficiency of filaggrin encoded by the FLG gene, leads to impaired epidermal barrier. Filaggrin expression reduced but mutations in the FLG gene have been reported to be rarely observed in psoriasis, therefore we suppose that FLG gene expression might be regulated by TET2, which is an alternative mechanism for barrier dysregulation in non-mutant FLG patients.