The skin circadian clock gene F3 as a potential marker for psoriasis severity and its bidirectional relationship with IL-17 signaling in keratinocytes

Abstract

Abstract Background Psoriasis is an immune-mediated skin disease where the IL-17 signaling pathway plays a crucial role in its development. Chronic circadian rhythm disorder in psoriasis pathogenesis is gaining more attention. The relationship between IL-17 signaling pathway and skin clock genes remains poorly understood. Methods GSE121212 with psoriatic lesion and healthy controls was used as exploration cohort for searching analysis. Datasets GSE117239, GSE51440, GSE137218 that contained effective biologics treating psoriasis overtime were applied to validation analysis. Single cell RNA sequencing (scRNA-seq) dataset GSE173706 were used to explore the F3 expression and related pathway activities in single cell levels. Through intersecting with high expression DEGs, F3 was selected as the signature skin circadian gene in psoriasis for further investigation. Functional analyses, including correlation analyses, prediction of transcription factors, protein-protein interaction, single gene GSEA to explore the potential roles of F3. ssGSEA algorithm was performed to uncover the immune related characteristics of psoriasis. We further explored F3 expression in specific cell population in scRNA-seq dataset, besides this, AUCell analysis was performed to explore the pathway activities and the results were further compared between specific cell cluster. Immunohistochemistry experiment, RT-qPCR was used to validate the location and expression of F3, small interfering RNA (siRNA) transfection experiment in HaCaT and transcriptome sequencing analysis were applied to explore the potential function of F3. Results F3 was significantly down-regulated in psoriasis and interacted with IL-17 signaling pathway. Low expression of F3 could upregulate the receptor of JAK-STAT signaling, thereby promoting keratinocytes inflammation. Conclusion Our research revealed a bidirectional link between the skin circadian gene F3 and the IL-17 signaling pathway in psoriasis, suggesting that F3 may interact with the IL-17 pathway by activating JAK-STAT within keratinocytes and inducing abnormal intracellular inflammation.