Lin Jin, Cao Yi, Ma Lili, Tao Maocan, Yang Xiaohong
Department of Dermatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People's Republic of China.
IUBMB Life. 2025 Jan;77(1):e2935. doi: 10.1002/iub.2935.
Keratinocytes exosome participates in the pathogenesis of psoriasis and exosomes always carry long non-coding RNAs (lncRNAs) into target cells to function as an essential immune regulator in psoriasis-related diseases. LncRNA LOC285194 is closely associated with the occurrence of psoriasis. However, whether keratinocyte exosomal LOC285194 participates in the process of psoriasis remains vague. Exosomes were authenticated by transmission electron microscope and nanoparticle tracking analysis (NTA). Relative gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry was used to monitor the proportion of immune cells. Fluorescence in situ hybridization was employed to determine the colocalization of lncRNA and miRNA. Keratinocyte exosomal LOC285194 was reduced in psoriasis patients and had a negative association with Th17 cell infiltration in psoriasis patients. LOC285194-downregulation contributed to the differentiation of CD4T cells to Th17 cells. Cytokine cocktail treatment reduced LOC285194 expression in keratinocytes and keratinocyte exosome, subsequently promoted the differentiation of CD4T cells to Th17 cells and Th17 cells-related molecular levels including IL-17A, IL-22 and TNF-α, which were notably abrogated by LOC285194-upregulation in keratinocytes. As a sponge of LOC285194, miR-211-5p inhibition induced the increase of Th17 cell proportion in CD4T cells, while exosomes treatment isolated from cytokine cocktail-exposed keratinocytes further enhanced Th17 cell proportion, which were abolished by LOC285194 overexpressed-exosome treatment. Furthermore, silent information regulator 1 (SIRT1) mediated the regulation role of miR-211-5p on Th17 cell production. Combined with the imiquimod-induced psoriasis animal model, exosomes isolated from LOC285194-overexpressing keratinocytes relieved psoriasis symptom through regulating miR-211-5p/SIRT1 axis. LOC285194 upregulation in keratinocytes promoted the keratinocyte exosomal LOC285194, that could be absorbed by CD4T cells, leading to the inhibition of Th17 cell differentiation through targeting miR-211-5p/SIRT1 axis. This study provides a novel molecular mechanism of Th17 cell accumulation-mediated psoriasis.
角质形成细胞外泌体参与银屑病的发病机制，且外泌体总是携带长链非编码RNA（lncRNA）进入靶细胞，在银屑病相关疾病中作为重要的免疫调节因子发挥作用。LncRNA LOC285194与银屑病的发生密切相关。然而，角质形成细胞外泌体中的LOC285194是否参与银屑病的发病过程仍不清楚。通过透射电子显微镜和纳米颗粒跟踪分析（NTA）对外泌体进行鉴定。采用逆转录-聚合酶链反应（RT-PCR）测定相关基因表达。利用流式细胞术监测免疫细胞比例。采用荧光原位杂交技术确定lncRNA与miRNA的共定位。银屑病患者角质形成细胞外泌体中的LOC285194减少，且与银屑病患者Th17细胞浸润呈负相关。LOC285194下调促进CD4T细胞向Th17细胞分化。细胞因子鸡尾酒处理降低角质形成细胞和角质形成细胞外泌体中LOC285194的表达，随后促进CD4T细胞向Th17细胞分化以及Th17细胞相关分子水平（包括IL-17A、IL-22和TNF-α）的升高，而角质形成细胞中LOC285194上调可显著消除这些变化。作为LOC285194的海绵，抑制miR-211-5p可诱导CD4T细胞中Th17细胞比例增加，而从细胞因子鸡尾酒处理的角质形成细胞中分离的外泌体处理可进一步提高Th17细胞比例，而过表达LOC285194的外泌体处理可消除这些变化。此外，沉默信息调节因子1（SIRT1）介导miR-211-5p对Th17细胞产生的调节作用。结合咪喹莫特诱导的银屑病动物模型，从过表达LOC285194的角质形成细胞中分离的外泌体通过调节miR-211-5p/SIRT1轴缓解银屑病症状。角质形成细胞中LOC285194上调促进角质形成细胞外泌体中的LOC285194，其可被CD4T细胞吸收，通过靶向miR-211-5p/SIRT1轴抑制Th17细胞分化。本研究提供了一种Th17细胞积累介导银屑病的新分子机制。
