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Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This in vitro study using normal human epidermal keratinocytes examined transcriptome changes induced by the antimicrobial peptide LL-37, implicated in rosacea, a chronic inflammatory facial skin disease. LL-37 treatment upregulated interferon-stimulated genes including CXCL10, IFIT2, RSAD2, and CXCL11, with gene ontology analysis showing activation of responses to bacterial-origin molecules, chemokines, and cytokine signaling, and pathway analysis showing activation of TNF, IL-17, NF-kB, and chemokine signaling. CXCL10 was the most abundantly upregulated inflammatory mediator, and its production was reported to depend on the Jak1/STAT1 signaling pathway, described by the authors as a link between keratinocytes and T-cell recruitment relevant to rosacea pathogenesis.
Abstract
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.
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