AhR-Notch通路介导人皮脂腺细胞异常分化在反常性痤疮发生中的作用及机制研究

Acne inversa (AI) is a common chronic inflammatory dermatosis with follicular occlusion. 90% of AI patients have a history of smoking, but the mechanism of cigarette-induced AI is unclear. It has recently been found that mutations in the gamma secretase (GS) gene result in inhibition of Notch pathway, which may be involved in the hyperkeratosis of hair follicle. We previously found that the sebaceous gland volumes were reduced or even disappeared in the skin lesions of AI patients, and the aryl hydrocarbon receptor (AhR) negatively regulated the stem cell characteristics of human sebocytes differentiated into keratinocytes, which is associated with the hyperkeratosis of hair follicle epithelium. Benzopyrene (BaP) in cigarettes could inhibit lipid synthesis by activating AhR, and inhibit Notch1-4 expressions in sebocytes. In combination with the literature reported that GS or Notch pathway-deficient mice showed reduced lipid synthesis or even loss of sebaceous gland，and the synergistic regulation of cell differentiation of AhR and Notch pathways. We hypothesized that BaP may inhibit the Notch pathway through AhR, induce sebocytes differentiated into keratinocytes, and then cause follicular keratinization and AI. We propose to use the AI patient skin lesions, in vitro skin 3D model and sebocytes to study the role of BaP-AhR-Notch pathway in regulating the abnormal differentiation of human sebocytes, which would probably provide a theoretical basis for elucidating the mechanisms and new therapeutic targets of AI.

反常性痤疮（AI）是常见的毛囊闭锁性慢性炎症性皮肤病。90%AI患者有吸烟史，但香烟诱发AI机制不清。近来发现γ分泌酶（GS）基因突变导致Notch通路抑制可能参与毛囊过度角化。我们前期发现：AI患者皮损存在皮脂腺体积缩小/消失，芳香烃受体（AhR）负性调节具有干细胞特性的人皮脂腺细胞向角质形成细胞分化并与毛囊上皮过度角化有关，香烟中苯并芘（BaP）激活AhR抑制皮脂腺细胞脂质合成与Notch1-4表达。结合文献GS或Notch通路缺陷小鼠皮脂腺脂质合成减少甚至缺失及AhR与Notch通路协同调节细胞分化进程的报道。我们推测：BaP可能通过AhR抑制Notch通路，诱导皮脂腺细胞向角质形成细胞分化进而导致毛囊角化及AI发生。拟采用AI患者皮损、体外皮肤3D模型及皮脂腺细胞，研究BaP-AhR-Notch通路在调节人皮脂腺细胞异常分化中的作用，为阐明AI发生机制及新的治疗靶位提供理论依据。

反常性痤疮（AI）是常见的毛囊闭锁性慢性炎症性皮肤病。90%AI患者有吸烟史，但香烟诱发AI机制不清。近来发现γ分泌酶（GS）基因突变导致Notch通路抑制可能参与毛囊过度角化。本次课题资助下我们首先研究了散发性AI患者皮肤组织标本中AhR和Notch信号通路表达情况，同时成功建立了体外3D皮肤皮脂腺模型；体外研究了香烟烟雾提取物（CSE）及其代表物苯并芘（BaP）和Notch通路激动剂白藜芦醇(RVT)在皮脂腺细胞脂质合成及炎症效应中的作用和相关通路的表达变化情况；研究了炎症因子IL-6对SZ95人皮脂腺细胞脂质合成的影响及可能机制。结果发现：1. 散发性AI患者皮肤组织标本中AhR通路被抑制，吸烟能够上调AhR通路的表达，而Notch通路则变化不明显；2. CSE体外抑制SZ95人皮脂腺细胞的脂质合成、促进炎症因子表达；3. BaP体外抑制SZ95人皮脂腺细胞及HaCaT人角质形成细胞的Notch信号通路；4. RVT体外能改善BaP等外源性刺激诱导的皮脂腺细胞炎症反应；5. RVT能够改善亚油酸（LA）诱导的皮脂腺细胞脂质聚集；6. IL-6体外通过PI3K/Akt信号通路诱导皮脂腺细胞的脂质合成增加。本研究结果明确了AhR及Notch通路在反向痤疮患者皮损中的表达变化情况，明确了BaP和Notch通路激动剂RVT在皮脂腺细胞脂质合成及炎症效应中的作用，脂质合成是皮脂腺细胞终末分化标记，初步明确了Notch通路参与调节皮脂腺细胞的脂质合成，BaP通过AhR和Notch信号途径在皮脂腺细胞分化中的作用，相关结果为进一步指导反向痤疮及相关疾病的临床诊疗提供了新的思路。