Inhibition of BRD4 inhibits proliferation and promotes apoptosis of psoriatic keratinocytes

Xiaohui Sun,Pengfei Yang

doi:10.1186/s12938-021-00943-y

Abstract

BackgroundPsoriasis is a common chronic recurrent inflammatory skin disease. The pathogenesis of psoriasis, such as other autoimmune diseases, is still unclear, which brings great difficulties to the treatment. This study aimed to investigate the role of bromine domain protein 4 (BRD4) in affecting the psoriatic keratinocytes.MethodsImiquimod-induced psoriasis mice model and TNF-α or IL-17A induced HaCAT cells, an experimental model in vitro for psoriasis, were constructed. The pathological skin changes at the back of mice were observed by hematoxylin and eosin (H&E) assay and evaluated by psoriasis area and severity index (PASI). KI67 expression and keratinocyte apoptosis at the skin tissues were, respectively, detected by Immunohistochemical analysis and TUNEL assay. The inflammatory factors in mice serum and culture supernatant were determined by ELISA assay. The related proteins expression of proliferation, apoptosis and MAPK pathway were detected by Western blot analysis.ResultsBRD4 expression was upregulated in injured skin on the back of imiquimod-induced mice and (+)-JQ1 relieved the skin injury by suppressing the inflammation and promoting apoptosis of keratinocytes. Consistently, BRD4 expression was also increased in TNF-α or IL-17A induced HaCAT cells. (+)-JQ1 suppressed the viability and inflammation, and promoted apoptosis of TNF-α or IL-17A induced HaCAT cells. In addition, the MAPK signaling pathway was inhibited by (+)-JQ1 whether in mice or HaCAT cells.ConclusionsInhibition of BRD4 inhibited proliferation and inflammation and promoted apoptosis of psoriatic keratinocytes.

Highlights

Psoriasis is a common chronic recurrent inflammatory skin disease
bromine domain protein 4 (BRD4) expression was upregulated in injured skin on the back of imiquimod‐induced mice The skin was damaged on the back of mice induced by imiquimod for 7 days compared with control group (Fig. 1A)
(+)‐JQ1 decreased the release of inflammatory factors in serum and increased the apoptosis of keratinocytes of imiquimod‐induced mice The levels of inflammatory factors (IFN-γ, IL-8 and IL-6) in serum of imiquimodinduced rat were increased and (+)-JQ1 or methotrexate could suppress the inflammation (Fig. 3A)

Summary

Introduction

Psoriasis is a common chronic recurrent inflammatory skin disease. The pathogenesis of psoriasis, such as other autoimmune diseases, is still unclear, which brings great difficulties to the treatment. Psoriasis is a chronic inflammatory skin disease. Psoriasis is associated with many diseases, such as hypertension, diabetes and metabolic syndrome [1,2,3]. The manifestations of psoriasis vulgaris include epidermal hyperkeratosis and paraceratosis, vascular. The pathogenesis of psoriasis is still unclear. Current systematic treatment measures for psoriasis include methotrexate (MTX), cyclosporin A, auxin, biologics, and sometimes steroids for patients with moderate to severe psoriasis, but these drugs have obvious side effects and adverse reactions, such as bone marrow suppression, abnormal liver function and metabolic disorders [5]. It is urgent to explore new effective therapeutic drugs for psoriasis

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