病原相关分子模式通过AHR-Nrf2通路诱导人皮脂腺细胞异常分化在寻常痤疮发生及转归中作用与机制研究

Atrophy of sebaceous glands in acne comedones is associated with spontaneous resolution of acne vulgaris with unknown mechanisms. In our previous studies we found that aryl hydrocarbon receptor(AHR) has bilateral modulation to differentiation of human sebocytes inducing sebocytes differentiate into keratinocytes line, and microorganisms p.acnes and PGN could inhibit the linoleum acid induced secretion of sebocytes and activated AHR signal pathway. In combination with the recent reports that the activation of AHR downstream genes Nrf2 and EGFR were related to abnormal differentiation of sebaceous glands and comedones formation, we speculate that the microorganisms in the pilosebaceous unit are the negative regulator which is related to acne pathogenesis and its spontaneous resolution. Overproduction of sebum with proliferation of microorganisms can active TLRs mediated innate immunity which is related to acne inflammation,but at the same time they also induce the abnormal sebaceous differentiation into keratinocytes lines with atrophy of glands via AhR-Nrf2-EGFR signal pathway in the price of epidermal hyperplasia and possible comedones formation. To prove this we intend to study the effects of pathogen-related molecular patterns (PAMPS) PGN , LPS and LTA on differentiation and sebum production ,as well as their activation on AHR-Nrf2-EGFR pathway, by using the condones lesions of acne patients, the in vitro skin 3D model culture and the SZ95 sebocytes culture model. This study will provide new evidences for the role of the atrophic sebaceous gland and its possible reasons ,as well as a new theory and molecular targets for acne pathogenesis, resolution , prevention and treatment in the future.

寻常痤疮粉刺中皮脂腺存在萎缩并与皮损自我转归有关，机制不清。前期发现芳香烃受体（AHR）双向调节人皮脂腺细胞向角质形成细胞分化，痤疮丙酸杆菌（P.acnes）及肽聚糖体外激活AHR并抑制皮脂腺脂质分泌，结合近来AHR下游基因Nrf2-EGFR激活与皮脂腺异常分化及粉刺形成有关的报道，我们推测：毛囊中微生物是皮脂腺脂质分泌负反馈调节因素并与痤疮发生及转归有关，脂质分泌伴随的微生物增殖在激活天然免疫同时通过AHR-Nrf2-EGFR通路诱导人皮脂腺细胞异常分化，但以表皮增生进而粉刺形成为代价。研究拟采用痤疮患者粉刺皮损、皮肤3D培养及皮脂腺细胞培养等模型，结合基因转染等分子技术，观察病原相关分子模式肽聚糖,脂多糖及磷壁酸对人皮脂腺细胞AHR-Nrf2-EGFR通路激活情况及对皮脂腺细胞分化影响，为研究痤疮粉刺中皮脂腺萎缩形成原因提供新线索，为阐明痤疮发生和转归机制及临床防治提供新思路。

寻常痤疮是一种常见的好发于面部的毛囊皮脂腺单位慢性炎症性皮肤疾病，青春期皮脂腺脂质大量分泌及嗜脂的痤疮丙酸杆菌等毛囊微生物增殖是痤疮发生的重要因素，但二者之间关系及其在痤疮中的作用和机制仍然不清。我们采用痤疮患者皮损、体外3D皮脂腺皮肤模型和皮脂腺细胞培养等研究模型，探索了毛囊微生物与皮脂腺脂质合成及细胞分化之间关系。研究发现：1.痤疮丙酸杆菌及病原相关分子模式（PAMPs）具有诱导皮脂腺细胞向角质形成细胞分化的作用；2. 痤疮丙酸杆菌及PAMPs中的PGN能激活皮脂腺细胞上的芳香烃受体（AHR）及Nrf2-EGFR信号通路，并诱导皮脂腺细胞向角质形成细胞分化；3. 痤疮丙酸杆菌及PGN体外对表皮细胞增殖和分化具有调节作用；4. 抗痤疮药物白藜芦醇、米诺环素及Clascoterone等通过影响相关信号通路进而参与调节PGN介导的皮脂腺细胞分化、脂质合成及相关炎症反应。研究结果显示，痤疮早期随着皮脂分泌的增多及痤疮丙酸杆菌等微生物增殖，细菌壁上的小分子PAMPs及部分细菌代谢产物可能在激活天然免疫的同时也激活皮脂腺细胞的AHR及Nrf2-EGFR信号通路，诱导皮脂腺细胞向角质形成细胞分化进而反馈性的抑制皮脂腺细胞脂质合成，该作用显示毛囊中的微生物不仅仅与炎症启动有关，还参与了皮脂腺分化及相关病理生理过程，提示我们毛囊中的正常微生物不仅是痤疮的致病因素，同时也是痤疮皮损自我转归的重要保护性因素，痤疮治疗不应以完全消灭毛囊微生物为目的。本研究为毛囊微生物与皮脂腺之间的关系及其在痤疮病理生理中的作用提供了新的假设和依据，也为痤疮未来防治提供了新的治疗靶点。