INVESTIGATIVE REPORT
585 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Ten-eleven Translocation-2 Regulates DNA Hydroxymethylation Status and Psoriasiform Dermatitis Progression in Mice
Xin WANG 1, 2 #, Xinxin LIU 1 #, Xiaoru DUAN 1, Ke ZHU 1, Song ZHANG 1, Lu GAN 1, Nian LIU 1, Himanshu JAYPAUL 1, Johanna T. MAKAMURE 1, Zhangyin MING 3 and Hongxiang CHEN 1
1
Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China, 2 Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China, and 3 Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
#
These authors contributed equally to this work.
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-γ) 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.
Key words: ten-eleven translocation 2; 5-hydroxymethylcytosine; psoriasis; epigenetics; Th17 cell.
Accepted Mar 15, 2018; Epub ahead of print Mar 15, 2018 Acta Derm Venereol 2018; 98: 585 – 593.
Corr: Hongxiang Chen, Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277 #, Wuhan 430022, China. E-mail: hongxiangchen @ hotmail. com
Psoriasis is a common chronic inflammatory skin disease associated with well-demarcated, erythematous plaques and silvery scales( 1). The pathogenic manifestations of psoriasis are characterized by immune cell infiltration and the aberrant proliferation and differentiation of epidermal cells( 2). Although the aetiology of psoriasis is incompletely understood, the interplay between genetic and environmental triggers is known to have an important role in the development of psoriasis( 3). Some studies have suggested that abnormal DNA methylation is present in psoriatic skin compared with normal or uninvolved psoriatic skin( 4, 5). However,
SIGNIFICANCE
Psoriasis is one of the most common chronic inflammatory skin diseases which is a complex disorder involving multiple pathogenic factors. This study explored the role of epigenetic modifications in the pathogenesis of psoriasis. Our study found that 5-hydroxymethylcytosine and ten-eleven translocation-2( TET2) levels were increased in psoriatic lesions, compared with normal skin. Knockdown of TET2 expression alleviated the severity of imiquimod-induced psoriasiform dermatitis in mice. Our data highlight a possible role for TET2 in the pathogenesis of psoriasiform dermatitis.
DNA hydroxymethylation and the mechanisms of psoriasis remain poorly understood.
Epigenetic modifications, such as DNA methylation, DNA hydroxymethylation and histone modifications, are crucial for regulating the occurrence and development of a variety of skin diseases, such as systemic lupus erythematosus. This suggests a significant role for epigenetic regulation in dermatology( 6, 7). Recently, several studies in both human and mice have identified that the ten-eleven translocation( TET) family dioxygenases TET1, TET2 and TET3 oxidize 5-methylcytosine( 5-mC) to 5-hmC, 5-formylcytosine( 5-fC) and 5-carboxylcytosine( 5-caC) in DNA, and promote DNA demethylation( 8 – 10). The newly characterized 5-hmC is commonly differentially expressed in various types of disorders. TET2 is expressed in several differentiated tissues and has been studied in a variety of diseases, such as haematopoietic diseases, immune system disorders and cancer( 11 – 14). TET2 has been positively associated with 5-hmC and regulation of other elements( 15). Dysregulation of TET2 affects diverse biological processes, including cell differentiation, development, and proliferation, indicating that TET2 is a key epigenetic regulating factor.
Although TET2 functions as a tumour suppressor within the hematopoietic system( 13), it is unclear whether TET2 is involved in the pathogenesis of psoriasis. TET2 has been shown to be associated with enriched areas of 5-hmC and to promote signature cytokine expression patterns of Th1 and Th17 cells( 12). TET2 selectively mediates transcription of IL-6 during inflammation resolution in dendritic cells by recruiting Hdac2
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2926 Acta Derm Venereol 2018; 98: 585 – 593