CD36-SREBP1 axis mediates thymic stromal lymphopoietin production in
obesity-exacerbated atopic dermatitis
Abstract
Background: Obesity is associated with an increased risk
of atopic dermatitis (AD) and may accelerate its development.
Keratinocyte dysfunction has been observed in obesity-related skin
diseases, including psoriasis and acanthosis nigricans, but is not fully
understood in AD. Here, we aim to emphasize the important role of
keratinocytes in obesity-aggravated AD. Methods: C57BL/6
mice were fed a high-fat diet (HFD) for 12 weeks before calcipotriol
(MC903) administration to induce AD-like dermatitis. Fatty acid intake
was quantified using BODIPY 500/510 staining. Palmitic acid (PA)
treatment of keratinocytes mimicked the obese state at the cellular
level. CD36 or sterol-regulatory element binding protein1 (SREBP1)
inhibitors were topically applied to mouse ears to explore the roles of
CD36 or SREBP1 in obesity-aggravated AD. A chromatin immunoprecipitation
assay (ChIP) was conducted to assess the transcriptional control of
SREBP1 on thymic stromal lymphopoietin ( TSLP) expression.
Results: HFD-induced obesity exacerbated AD-like
dermatitis in mice, with elevated inflammatory molecules and fatty acid
accumulation in the lesional skin. Blocking CD36, a fatty acid
transporter, with a chemical antagonist effectively alleviated AD-like
inflammation and decreased TSLP levels in obese MC903-treated mice.
Moreover, PA treatment induced TSLP overexpression via CD36 and
activated the downstream SREBP1 signaling pathway in keratinocytes. The
ChIP assay further revealed increased binding of SREBP1 to the
TSLP promoter region. Conclusion: Obesity
activates the CD36-SREBP1-TSLP axis in keratinocytes, inducing epidermal
lipid disorders and aggravating AD-like inflammation. Targeting CD36 or
SREBP1 will facilitate the development of future combination therapies
or modified therapies for treating patients with obesity and AD.