Gao Pengfei, Gao Xiaolu, Lin Long, Zhang Ming, Luo Dongqiang, Chen Chuyan, Li Yujie, He Yufeng, Liu Xianmiao, Shi Chunyu, Yang Ruisi
School of Yunkang Medicine and Health, Nanfang College, Guangzhou, People's Republic of China.
Biomedical Big Data Center, Nanfang College, Guangzhou, People's Republic of China.
J Inflamm Res. 2025 May 22;18:6557-6582. doi: 10.2147/JIR.S521553. eCollection 2025.
Psoriasis is an immune-mediated skin disease where Th17 cell differentiation and IL-17 secretion play critical roles. This study investigates key exosomal ncRNAs regulating the Th17/IL-17 axis in psoriasis and their mechanisms.
We integrated bulk RNA sequencing datasets from the GEO database to construct and evaluate exosome-related patterns. Subsequently, exosome-related ncRNAs in psoriasis lesions were identified primarily through weighted gene co-expression network analysis and five machine learning algorithms. Additionally, large-scale integrated single-cell RNA sequencing data and genome-wide association study (GWAS) data were included to investigate the mechanisms of key ncRNA, primarily through immune infiltration analysis, gene set enrichment analysis (GSEA), co-expression analysis, and Mendelian randomization. Finally, the mechanisms of key ncRNA were confirmed primarily through cell co-culture and lentiviral transfection, assessed by immunofluorescence, qRT-PCR, and Western blot.
We identified 10 exosome-related ncRNAs, including PRKCQ-AS1, and constructed five machine learning models with excellent diagnostic performance, emphasizing PRKCQ-AS1's significance. Mendelian randomization demonstrated a causal relationship between PRKCQ-AS1 and psoriasis. Immune infiltration analysis and GSEA indicated that PRKCQ-AS1 influences the infiltration pattern of CD4T cells, promotes Th17 differentiation, and is related to STAT3. The expression distribution in single-cell RNA sequencing data suggested that exosomal PRKCQ-AS1 may originate from keratinocytes, and co-expression analysis supported its role in STAT3 activation within lymphocytes. Co-culture experiments confirmed that keratinocytes in psoriasis models, as well as keratinocytes overexpressing PRKCQ-AS1, can upregulate PRKCQ-AS1 levels in CD4T cells via exosomes, promoting Th17 cell differentiation and IL-17 secretion. Consistent results and STAT3 signaling pathway activation were detected in CD4T cells overexpressing PRKCQ-AS1.
PRKCQ-AS1 is an exosomal lncRNA from keratinocytes in psoriasis, promoting Th17 differentiation and IL-17 secretion through STAT3 activation. This finding deepens the understanding of psoriasis pathogenesis and provides a basis for targeted therapies.
银屑病是一种免疫介导的皮肤病，其中Th17细胞分化和白细胞介素-17（IL-17）分泌起着关键作用。本研究调查了调节银屑病中Th17/IL-17轴的关键外泌体非编码RNA（ncRNAs）及其机制。
我们整合了来自基因表达综合数据库（GEO数据库）的大量RNA测序数据集，以构建和评估外泌体相关模式。随后，主要通过加权基因共表达网络分析和五种机器学习算法，鉴定银屑病皮损中的外泌体相关ncRNAs。此外，纳入大规模整合单细胞RNA测序数据和全基因组关联研究（GWAS）数据，主要通过免疫浸润分析、基因集富集分析（GSEA）、共表达分析和孟德尔随机化来研究关键ncRNA的机制。最后，主要通过细胞共培养和慢病毒转染来证实关键ncRNA的机制，并通过免疫荧光、定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法进行评估。
我们鉴定出10种外泌体相关ncRNAs，包括蛋白激酶Cθ反义RNA1（PRKCQ-AS1），并构建了五个具有优异诊断性能的机器学习模型，突出了PRKCQ-AS1的重要性。孟德尔随机化证明PRKCQ-AS1与银屑病之间存在因果关系。免疫浸润分析和GSEA表明，PRKCQ-AS1影响CD4T细胞的浸润模式，促进Th17分化，并与信号转导和转录激活因子3（STAT3）相关。单细胞RNA测序数据中的表达分布表明，外泌体PRKCQ-AS1可能起源于角质形成细胞，共表达分析支持其在淋巴细胞内STAT3激活中的作用。共培养实验证实，银屑病模型中的角质形成细胞以及过表达PRKCQ-AS1的角质形成细胞，可以通过外泌体上调CD4T细胞中的PRKCQ-AS1水平，促进Th17细胞分化和IL-17分泌。在过表达PRKCQ-AS1的CD4T细胞中检测到一致的结果和STAT3信号通路激活。
PRKCQ-AS1是银屑病中角质形成细胞来源的外泌体长链非编码RNA，通过激活STAT3促进Th17分化和IL-17分泌。这一发现加深了对银屑病发病机制的理解，并为靶向治疗提供了依据。
