Ten-eleven Translocation-2 Regulates DNA Hydroxymethylation Status and Psoriasiform Dermatitis Progression in Mice

Abstract

Epigenetics plays an important role in the development and progression of many diseases. There is increasing evidence for the importance of epigenetic modifications in the progression of psoriasis. The aim of this study was to examine the role and potential mechanism of action of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation-2 (TET2) in psoriasiform dermatitis in mice. Immunohistochemical staining was performed on psoriasis patients and healthy controls. Topical application of imiquimod cream to the dorsal skin of mice was used to induce psoriasiform dermatitis. In comparison with healthy controls, 5-hmC was more extensive and intense in the skin lesions from psoriasis patients. TET2 and 5-hmC were highly expressed in imiquimod-induced psoriasiform skin lesions. Importantly, knockdown of TET2 expression in mice attenuated the psoriasiform phenotype and the expression levels of proinflammatory cytokines (interleukin-17A and -17F and interferon-?) and the chemokine CXCL1 in the lesional skin of mice. This is the first demonstration of a critical role for TET2 in psoriasiform dermatitis in a mouse model, and indicates that 5-hmC may serve as a potential biomarker of psoriasis.

TET2 is involved in DNA hydroxymethylation, cell proliferation and inflammatory response in keratinocytes

“…Wang et al (35), revealed that TET2 knockdown by siRNAs not only affected the level of MyD88 innate immune signal transduction adaptor hydroxymethylation, but also inhibited lipopolysaccharide-induced inflammation in human dental pulp cells. Our previous study suggested that TET2 modulates the expression of proinflammatory cytokines in a mouse model of psoriasiform dermatitis (24). In the present study, the effects of DNA demethylation on inflammatory factors were examined in vitro.…”

“…However, the role of TET2 in skin disease remains unclear. Our previous study reported that 5-hmC and TET2 levels were increased in epidermal keratinocytes in psoriasiform dermatitis (24). To further investigate the function of TET2 in inflammatory skin diseases, the present study performed experiments using the keratinocyte HaCaT cell line.…”

ANGPTL4 Regulates Psoriasis via Modulating Hyperproliferation and Inflammation of Keratinocytes

“…Other details were described in Figure 9A . According to the previous description, the Psoriasis Area and Severity Index (PASI) scores of mouse back skin were assessed by two laboratory assistants who did not know the group information ( Wang et al, 2018 ). On the eighth day, plasma samples and the back skin was separated from the sacrificed mice for subsequent detections.…”

Epigenetic Regulation of Epidermal Differentiation

“…The involvement of epigenetic factors in psoriasis, a chronic inflammatory disease characterized by hyperproliferation and incomplete differentiation/cornification of keratinocytes resulting in a thickened epidermis, has been intensively studied, and the published data give a good idea of their importance in this pathology. Analysis of psoriatic skin biopsies revealed dysregulation of multiple epigenetic mechanisms, including aberrant DNA methylation [ 41 ] and hydroxymethylation [ 42 , 43 ], alterations in histone modifications [ 44 ] and miRNA expression [ 45 ]. Interestingly, these differences could be observed not only between the skin of healthy individuals and psoriatic patients but also, although to a lesser extent, between patient’s uninvolved and lesional skin [ 45 , 46 , 47 , 48 ].…”