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Multi-Antigen Imaging Reveals Inflammatory DC, ADAM17 and Neprilysin as Effectors in Keloid Formation.

ABSTRACT: Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.

SUBMITTER: Rath M

PROVIDER: S-EPMC8430546 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundKeloid is a benign fibro-proliferative dermal tumor formed by an abnormal scarring response to injury and characterized by excessive collagen accumulation and invasive growth. The mechanism of keloid formation has not been fully elucidated, especially during abnormal scarring. Here, we investigated the regulatory genes, micro-RNAs (miRNAs) and transcription factors (TFs) that influence keloid development by comparing keloid and normal scar as well as keloid and normal skin.MethodsGene expression profiles (GSE7890, GSE92566, GSE44270 and GSE3189) of 5 normal scar samples, 10 normal skin samples and 18 keloid samples from the Gene Expression Omnibus (GEO) database were interrogated. Differentially expressed genes (DEGs) were identified between keloid and normal skin samples as well as keloid and normal scar samples with R Project for Statistical Computing. Gene Ontology (GO) functional enrichment analysis was also performed with R software. DEG-associated protein-protein interaction (PPI) network was constructed by STRING, followed by module selection from the PPI network based on the MCODE analysis. Regulatory relationships between TF/miRNA and target genes were predicted with miRnet and cytoscape. Core regulatory genes were verified by RT-qPCR.ResultsWe identified 628 DEGs, of which 626 were up-regulated and 2 were down-regulated. Seven core genes [neuropeptide Y(NPY), 5-hydroxytryptamine receptor 1A(HTR1A), somatostatin (SST), adenylate cyclase 8 (ADCY8), neuromedin U receptor 1 (NMUR1), G protein subunit gamma 3 (GNG3), and G protein subunit gamma 13 (GNG13)] all belong to MCODE1 and were enriched in the "G protein coupled receptor signaling pathway" of the GO biological process category. Furthermore, nine core miRNAs (hsa-mir-124, hsa-let-7, hsa-mir-155, hsa-mir-26a, hsa-mir-941, hsa-mir-10b, hsa-mir-20, hsa-mir-31 and hsa-mir-372), and two core TFs (SP1 and TERT) were identified to play important roles in keloid formation. In the TF/miRNA-target gene network, both hsa-mir-372 and hsa-mir-20 had a regulatory effect on GNG13, ADCY8 was predicted to be target by hsa-mir-10b, and HTR1A and NPY were potentially by SP1. Furthermore, the expression of core regulatory genes (GNG13, ADCY8, HTR1A and NPY) was validated in clinical samples.ConclusionsGNG13, ADCY8, NPY and HTR1A may act as core genes in keloid formation and these core genes establish relationship with SP1 and miRNA (hsa-mir-372, hsa-mir-20, hsa-mir-10b), which may influence multiple signaling pathways in the pathogenesis of keloid.

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Multi-Antigen Imaging Reveals Inflammatory DC, ADAM17 and Neprilysin as Effectors in Keloid Formation.

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