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Immune-related gene expression in skin, inflamed and keloid tissue from patients with keloids.

ABSTRACT: Keloids are a tumor-like fibroproliferative skin disease that could cause disfigurement and disability. The pathological mechanisms underlying this condition remain unclear, particularly the progression from normal healthy skin to inflammatory skin tissue, then keloid. In the present study, three immune-related gene expression profiling datasets, were obtained from normal skin tissue (N group), inflamed tissue (I group) and keloid tissue samples from patients with keloids (K group). This sample grouping represents the primary steps of keloid formation, from normal to inflammatory, and finally to keloid tissue. The expression levels of immune-related genes were analyzed, and the differentially expressed genes (DEGs) between the three groups were compared. Protein-protein interaction networks were established using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out to determine the main functions associated with the DEGs and keloid-associated pathways. The results identified hub genes in the N and I groups, including C-C motif chemokine receptor (CCR) 1, CCR7, CD40 ligand, C-X-C motif chemokine ligand 9, IL-6 and IL-10. The hub genes in the I and the K groups included IL-10, IL-6, IL-13 and CD86. The expression levels of these genes were verified using reverse transcription-quantitative PCR. The results demonstrated that IL-6 expression levels were significantly increased in the I group compared with the N group (P=0.0111). CCR7 levels significantly differed between all three groups (P<0.017). The results of GO analysis suggested that the hub genes in the I and N groups may be associated with 'regulation of lymphocyte activation' and 'T-cell activation'. Similar results were also observed between the I and K groups, which may play an important role in keloid initiation and formation. In conclusion, CCR7, IL-10 and IL-6 may be important in keloid initiation and formation. These findings provided insight into the pathogenesis of keloids and may help identify novel immune-related therapeutic targets for this condition.

SUBMITTER: Shan M

PROVIDER: S-EPMC8756427 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundKeloids are a common complication of wounds, often manifesting with continuous hyperplasia and aggressive growth. Keloids also have a high recurrence rate and are largely resistant to treatment, making them clinically incurable, highlighting the need to translate basic research into clinical practice.Materials and methodsWe used GSE158395 and GSE92566 as discovery datasets to identify specific enriched hub genes and lncRNAs associated with keloid development and progression. This data was then used to identify the competing endogenous RNAs (ceRNAs) in these pathways by using a bidirectional selection method. Then, all hub genes and lncRNAs in ceRNAs were validated using GSE90051, GSE178562, and GSE175866, which describe the transcriptional profiles of keloid tissues, fibroblasts from pathological scars, and keloid fibroblast subpopulations, respectively. The keloid tissues were measured with qPCR.ResultsBoth fat-associated biological processes and fat cell differentiation were enriched in the downregulated gene set. Further evaluation revealed that all 11 hub genes were lipo-related, and most of these were differentially expressed in all three validation datasets. We then identified a clear ceRNA network within the data comprising six hub genes and four lncRNAs. Evaluations of the validation datasets confirmed that all six of these hub genes and two of the four lncRNAs were downregulated in keloid tissues; two hub genes and one lncRNA were downregulated in fibroblasts from pathological scars; and five hub genes and one lncRNA were significantly downregulated in mesenchymal subpopulation. Three genes had statistical difference and eight genes showed downregulated trend through qPCR of the keloid tissue.ConclusionOur results suggest that keloid development relies on the downregulation of lipo-related genes and pre-adipocytes in diseased tissues and may be one of the key mechanisms underlying fat grafting-mediated treatment of pathological scarring.

Project description:A keloid is a fibroproliferative disorder of unknown etiopathogenesis that requires ill-defined treatment. Existing evidence indicates that the immune system plays an important role in the occurrence and development of keloid. However, there is still a lack of research on the immune-related signatures of keloid. Here we identified immune-related signatures in keloid and explored their pathological mechanisms. Transcriptomic datasets (GSE7890, GSE92566, and GSE44270) of keloid and normal skin tissues were obtained from the Gene Expression Omnibus database. The overlap of differentially expressed genes and immune-related genes was considered as differentially expressed immune-related genes (DEIGs). Functional analysis, expression, and distribution were applied to explore the function and characteristics of DEIGs, and the expression of these DEIGs in keloid and normal skin tissues was verified by immunohistochemistry. Finally, we conducted interactive network analysis and immune infiltration analysis to determine the therapeutic potential and immune correlation. We identified four DEIGs (LGR5, PTN, JAG1, and DKK1). In these datasets, only GSE7890 met the screening criteria. In the GSE7890 dataset, DKK1 and PTN were downregulated in keloid, whereas JAG1 and LGR5 were upregulated in keloid. In addition, we obtained the same conclusion through immunohistochemistry. Functional analysis indicated that these four DEIGs were mainly involved in stem cell, cell cycle, UV response, and therapy resistance. Through interactive network analysis, we found that these DEIGs were associated with drugs currently used to treat keloid, such as hydrocortisone, androstanolone, irinotecan, oxaliplatin, BHQ-880, and lecoleucovorin. Finally, many immune cells, including CD8+ T cells, resting memory CD4+ T cells, and M1 macrophages, were obtained by immune infiltration analysis. In conclusion, we identified four immune signaling molecules associated with keloid (LGR5, PTN, JAG1, and DKK1). These immune-related signaling molecules may be important modules in the pathogenesis of keloid. Additionally, we developed novel therapeutic targets for the treatment of this challenging disease.

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Immune-related gene expression in skin, inflamed and keloid tissue from patients with keloids.

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