TRPV3 mediates Propionibacterium acnes-induced chemotaxis and inflammation in sebocytes

TRPV3 is highly expressed in human skin and is involved in the development of inflammatory dermatoses. However, it remains unclear whether TRPV3 influences inflammation in human sebaceous glands and its role in the pathogenesis of acne. Here, we showed that TRPV3 expression was increased in the sebaceous glands of facial acne lesions and acne-like mice. TRPV3 increased the secretion of pro-inflammatory cytokines and chemokines in human SZ95 sebocytes, as well as the chemotaxis of neutrophils, which were the major immune cells found in acne lesions. We demonstrated that P.acnes promoted TRPV3 expression through regulating lipid profile especially upregulated arachidonic acid levels in human sebocytes. TRPV3 further upregulated TLR2 expression by promoting transcriptional factor p-FOSL1 expression and its binding to the TLR2 promoter, leading to downstream NF-κB signaling activation. Importantly, either genetic silencing or pharmacological inhibition of TRPV3 alleviated acne-like inflammation in mice, showing reduced acne-characteristic cytokines and chemokines production and neutrophil infiltration by inhibiting the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebocytes inflammation, which was involved in the development of acne, indicating that TRPV3 is a potential therapeutic target for acne and other disorders of the pilosebaceous unit. To investigate the role of TRPV3 in the inflammation of human sebocytes, we established TRPV3-overexpressed human sebocytes by transfecting either Mock or TRPV3-overexpression plasmids into human SZ95 sebocytes. Three biological replicates were used for each group.

瞬时受体电位香草酸亚型3（Transient Receptor Potential Vanilloid 3, TRPV3）在人体皮肤中高表达，并参与炎症性皮肤病的发生发展。然而，目前尚不清楚TRPV3是否会影响人体皮脂腺的炎症反应，以及其在痤疮发病机制中的作用。本研究发现，面部痤疮皮损及痤疮样模型小鼠的皮脂腺中，TRPV3的表达水平均显著升高。TRPV3可促进人SZ95皮脂腺细胞分泌促炎细胞因子与趋化因子，并增强中性粒细胞的趋化能力——而中性粒细胞正是痤疮皮损中主要的免疫细胞类群。本研究证实，痤疮丙酸杆菌（P.acnes）可通过调控人皮脂腺细胞的脂代谢谱，尤其是上调花生四烯酸（arachidonic acid）的水平，从而促进TRPV3的表达。TRPV3还可通过促进转录因子磷酸化FOS样抗原1（p-FOSL1）的表达及其与Toll样受体2（TLR2）启动子的结合，上调TLR2的表达，进而激活下游核因子κB（NF-κB）信号通路。尤为重要的是，无论是通过基因沉默还是药理学抑制手段靶向TRPV3，均可减轻模型小鼠的痤疮样炎症反应——具体表现为通过抑制TLR2-NF-κB信号轴，减少痤疮特征性细胞因子与趋化因子的分泌，同时降低中性粒细胞浸润程度。综上，本研究揭示了TRPV3在皮脂腺细胞炎症反应中的关键作用，该作用参与了痤疮的发生发展，提示TRPV3可作为痤疮及其他毛囊皮脂腺单位（pilosebaceous unit）相关疾病的潜在治疗靶点。为探究TRPV3在人皮脂腺细胞炎症反应中的作用，本研究通过将空载对照（Mock）质粒或TRPV3过表达质粒转染至人SZ95皮脂腺细胞，成功构建了TRPV3过表达的人皮脂腺细胞模型。每组实验均设置3次生物学重复。