The study shows that the skin protein LL-37 can make skin cells release a signal called CXCL10, which pulls in T‑cells and causes rosacea flare‑ups. This process needs the Jak1/STAT1 pathway, so blocking either CXCL10 or Jak1/STAT1 might calm the inflammation.

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.