Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway

Rosacea is a chronic inflammatory disease of facial skin with unknown pathophysiology. Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea. However, its significance in rosacea pathogenesis is not fully understood. We sought to understand the molecular mechanisms of LL-37–mediated rosacea-like inflammation in an in vitro model of normal human epidermal keratinocytes. Transcriptome profiling of LL-37–treated keratinocytes identified signatures of IFN-stimulating genes, such as CXCL10 , IFIT2 , RSAD2 , and CXCL11 among the top upregulated differentially expressed genes. Gene ontology enrichment of biological processes revealed activation of cellular response to molecules of bacterial origin, response to chemokines, and cytokine-mediated signaling pathways, whereas Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed the activation of TNF signaling, IL-17 signaling, NF-kB signaling, and chemokine signaling among the most significant pathways. Remarkably, T-cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure. Mechanistically, LL-37–induced CXCL10 production relied on the Jak1/signal transducer and activator of transcription 1 signaling pathway. In summary, our findings provide a crucial link to keratinocyte–T-cell crosstalk, and blockade of the CXCL10:CXCR3 axis or Jak1/signal transducer and activator of transcription 1 pathways can be an effective anti-inflammatory strategy to reduce rosacea inflammation by restricting pathogenic T-cell infiltration.