Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy.

Hye Ran Kim,Hye One Kim,Chun Wook Park,Jin Cheol Kim,Seok Young Kang,Bo Young Chung

doi:10.3390/ijms22083968

Abstract

Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.

Highlights

Psoriasis is a common chronic inflammatory skin disease that affects approximately1–3% of the population worldwide [1]
After 2 days of IMQ cream application, TCDD, rapamycin, or TCDD + rapamycin cream was applied in the morning for 4 days
Topical application of TCDD led to an increase in the severity of total cumulative scores as well as individual scores at 4 and 6 days compared with the IMQ group

Summary

Introduction

Psoriasis is a common chronic inflammatory skin disease that affects approximately. 1–3% of the population worldwide [1]. This disease is clinically characterized by welldemarcated erythematous scaly plaques at distinct sites or disseminated on the whole body [2]. Inflammation in psoriasis affects the skin and systemic circulation [3]. Psoriasis is a systemic inflammatory disease with a growing body of comorbidities, ranging from respiratory to cardiovascular and gastrointestinal diseases [4,5,6,7]. The inter-relation between concurrent inflammatory diseases such as asthma and psoriasis or liver diseases and psoriasis has been modelled [12,13]

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