Identification and characterization of four immune-related signatures in keloid

Abstract

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.

Commensal microbiome dysbiosis elicits IL-8 signaling to drive fibrotic skin disease

“…In current study, we pay our attention to human unique skin fibrotic disease-keloids, though lacking relevant animal models, and therefore difficult to study in terms of etiology and pathogenic mechanisms. While some genetic and environmental factors associated with keloid formation are identified (5,(7)(8)(9)(10)(11)(12), none of them can be considered as a main explanation. It is highly probable that the formation of keloids is indeed a resultant of multiple factors.…”

“…The initiation and support of this fibroblastic pathology remains elusive. Previous research indicates that keloids are related to genetic features (5,6), mechanical properties of the skin (7), nutrition and metabolism (8), composition of local hematopoietic compartment (9)(10)(11), and neuro-endocrine interactions (12).…”

Screening of keloid immune microenvironment-related genes and their effects on keloid proliferation and migration

“…Some researchers have reported that keloid broblasts can promote or inhibit keloid development through immune processes such as stress induced by immune cells in the microenvironment. In the analysis of keloid tissues, it was found that the number of macrophages, T cells, mast cells and Langerhans cells in keloid was signi cantly increased, and these immune cells could secrete cytokines to stimulate collagen production and promote scar process (Wilgus et al, 2020;Wang et al, 2022;Lv et al, 2020). Some researchers have also found that macrophages, Treg cells, CD 8+ T cells, dendritic cells and natural killer cells play an important role in the pathological process of keloid when analyzing keloid immune in ltration (Niessen et al, 2004).…”

Multimodal roles of transient receptor potential channel activation in inducing pathological tissue scarification

“…It is mainly characterized by the infiltration of inflammatory cells such as macrophages, lymphocytes, mast cells and neutrophils (3). Inflammatory mediators secreted by immune cells induce fibroblasts (FBs) fibrosis and keratinocytes (KCs) re-epithelialization, resulting in excessive deposition of a large amount of extracellular matrix (ECM) components, which is accompanied by mechanical stretching and angiogenesis and eventually develops into PS (4)(5)(6). Furthermore, recent studies have shown that oxidative stress and epigenetic regulation are involved in the occurrence of PS (7,8).…”