Keloid Disease Research Articles

PTB Regulates Keloid Fibroblast Migration and Proliferation Through Autophagy.

Keloid disease is a chronic fibroproliferative disease that occurs after tissue injury, and the currently available treatments are unsatisfactory. We aimed to explore the level of autophagy in keloid fibroblasts (KFbs) and adjacent normal fibroblasts (NFbs). In addition, whether polypyrimidine tract-binding protein (PTB) regulates the biological functions of KFbs via autophagy was also investigated. The morphology of fibroblasts in normal skin and keloids was observed transmission electron microscopy. We silenced PTB with PTB-specific siRNA to determine whether PTB-regulated KFb proliferation. Acridine orange and LysoTracker Red staining was performed to label acidic compartments. Interestingly, when autophagy was inhibited by wortmannin, the PTB knockdown-mediated decrease in KFb migration and proliferation was abolished, while the collagen I and III levels were not altered; these results indicated that PTB regulated the migration and proliferation of KFbs via autophagy, while collagen synthesis occurred independently of PTB regulation. Many activities related to the survival and function of KFbs are controlled by PTB. Transmission electron microscopy revealed more autophagosomes and autolysosomes in KFbs than in NFbs. PTB induced autophagy in KFbs, as demonstrated by the significantly greater number of autophagosomes in KFbs after PTB knockdown, which was revealed by acridine orange and LysoTracker staining. Our study is the first to show that PTB regulates the migration and proliferation of KFbs via autophagy and that PTB regulates collagen synthesis in KFbs in an autophagy-independent manner. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Decoding skin mysteries: Unveiling the link between microbiota and keloid scars through a Mendelian randomization study.

The cause of keloids remains unclear, but studies suggest a link between skin microbiota and keloid formation. However, the causal relationship has not been confirmed. This study utilized Genome-Wide Association Studies (GWAS) data from 2 population-based German cohorts, comprising a total of 1656 skin samples. To bolster the reliability of our results, we incorporated GWAS data from 3 keloid cohorts, encompassing 2555 patients and 870,556 controls (GWAS ID: keloid1, ebi-a-GCST90018874; keloid2, bbj-a-131; keloid3, ebi-a-GCST90018654). Subsequently, we employed bidirectional 2-sample Mendelian randomization (MR) analysis to probe the causal relationship between the variables. The primary method employed was the inverse-variance weighted (IVW) method, supported by heterogeneity analysis, horizontal pleiotropy testing, outlier detection, and "leave-one-out" sensitivity analysis. By synthesizing the results from 3 groups of MR analyses, we discovered a negative causal association between a.ASV063 [Finegoldia (unc.)] located on the volar forearm and keloid disease (IVW (keloid1) odds ratio (OR): 0.939, 95% confidence interval (CI): 0.886-0.994, P = .032; IVW (keloid2) OR: 0.897, 95% CI: 0.813-0.990, P = .031; IVW (keloid3) OR: 0.900, 95% CI: 0.825-0.981, P = .017). Similarly, a negative causal relationship may also exist between the genus: Bacteroides from the antecubital fossa and keloid disease (IVW (keloid1) OR: 0.928, 95% CI: 0.884-0.973, P = .002; IVW (keloid2) OR: 0.891, 95% CI: 0.820-0.968, P = .007; IVW (keloid3) OR: 0.918, 95% CI: 0.849-0.992, P = .030). Additionally, no reverse causation was found, with all analyses showing no signs of horizontal pleiotropy or heterogeneity. This study offers new insights for the prevention and treatment of keloids.

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

Wound healing is an intensely studied topic involved in many relevant pathophysiological processes, including fibrosis. Despite the large interest in fibrosis, the network that is related to commensal microbiota and skin fibrosis remains mysterious. Here, we pay attention to keloid, a classical yet intractable skin fibrotic disease to establish the association between commensal microbiota to scaring tissue. Our histological data reveal the presence of microbiota in the keloids. 16S rRNA sequencing characterizes microbial composition and divergence between the pathological and normal skin tissues. Moreover, the data show elevation of interleukin-8 (IL-8) in both the circulation and keloid tissue, which elicited the collagen accumulation and migratory program of dermal fibroblasts via CXCR1/2 receptor. Our research provides insights into the pathology of human fibrotic diseases, advocating commensal bacteria and IL-8 signaling as useful targets in future interventions of recurrent keloid disease.

Profibrotic Inflammatory Cytokines and Growth Factors Are Predicted as the Key Targets of Uncaria gambir (Hunter) Roxb. in Keloids: An Epistatic and Molecular Simulation Approach.

Keloid is characterized as the fibrotic tissue resulting from the increase of fibroblast activity. Uncaria gambir (Hunter) Roxb. possesses bioactive compounds that have potential as antifibrotic agents, while the mechanism of action in keloid has not yet been elucidated. The aim of this study was to investigate the interaction of gambir bioactive compounds with keloid target proteins using an epistatic and molecular simulation approach. The known bioactive compounds of gambir targets and keloid-related protein targets were screened using databases. The network was constructed and analyzed to obtain the core protein targets. The targets were enriched to describe the Gene Ontology (GO) and pathway related to the proteins. Eleven targets were defined as the main targets of gambir bioactive compounds related to keloid disease. Gambiriin C, Isogambirine, and Procyanidin B1 were identified as the most promising compounds with the highest binding energy to transforming growth factor beta 1 (TGFβ1), AKT serine/threonine kinase 1 (AKT1), and matrix metallopeptidase 1 (MMP1) as the target proteins. GO enrichment and pathway analysis found that gambir bioactive compounds may act on keloid-related target proteins to regulate cell proliferation, migration, transcription, and signal transduction activity via profibrotic cytokine and growth factor signaling pathways. This study provides a reference for potential targets, compounds, and pathways to explain the mechanism of gambir against keloid.

Abstract LB320: Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis

Abstract Cancer associated fibroblasts (CAFs) express a variety of cytokines and factors that activate and contribute to pathways that favor tumorigenesis. CAFs disrupt normal cellular functions, such as cell cycle regulation and cell death including apoptosis, or signal certain types of cells to abnormally activate pro-tumor activities. In addition, when it is abnormally activated, it is characterized by increased collagen deposition and more contractility. Likewise, This pattern of abnormal activation is often observed in keloid disease. Keloid constitutes an abnormal fibroproliferative wound healing response with excessive collagen deposition causing abnormal wound healing. To better understand the CAF subtypes with abnormal activation and cancer-promoting properties and the subtypes of keloid fibroblasts with similar activation properties, it is essential to find the master transcription factors (TFs) that determine their identity. To identify functionally important TFs in abnormal CAFs and keloid fibroblasts, we analyzed H3K27ac ChIP-seq of CAFs and keloid fibroblasts and observed that Runx2 significantly enriched the two types of abnormal fibroblasts.To investigate the biological function of Runx2 , we established CAFs from colon cancer patients and performed ShRNA-mediated knockdown of the RUNX2 gene. We confirmed that knockdown of RUNX2 in CAFs suppressed the migration or invasion of cancer cells. Additionally, using a gel contraction assay, we confirmed that fibroblast contractility was significantly reduced by RUNX2 knockdown. Similarly, in keloid fibroblasts, it was confirmed that the migration and gel contraception abilities of fibroblasts were significantly reduced following knockdown of RUNX2 [A1] gene. Last but not least, expression of ECM elements, such as collagens and fibronectin, were significantly as a result of the knockdown of the RUNX2 gene in both abnormally activated fibroblasts. To conclude, we believe that Runx2 acts as a key TF that maintains the contractility and ECM remodeling ability of abnormally activated fibroblasts. Our findings indicate that Runx2 is a attractive therapeutic target not only for pro-tumorigenesis in the cancer microenvironment, but also for keloid fibroblasts. Citation Format: Keun-Woo Lee, Insuk Sohn, Seok-Hyung Kim, So-Young Yeo. Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB320.

Effectiveness of combination use of intralesional steroid with 5-fluorouracil in the treatment of keloid patients

Background: Keloids are a common problem with significant recurrence rates despite intralesional steroid treatment and 5-fluorouracil in combination with triamcinolone may be superior to triamcinolone alone. Objectives: To evaluate the effectiveness of the combination use of intralesional steroids with 5-fluorouracil in the treatment of keloid. Methods: The study was a descriptive cross-sectional study and was conducted at the Department of Dermatology and Venereology, Khwaja Yunus Ali Medical College (KYAMC), Enayetpur, Sirajganj, from July 2020 to June 2021. A total of 100 patients with keloid were included in this study. These patients were subjected to history, clinical examination, and investigations. In all cases, informed written consent was taken from the Participants and a separate case record form was used during data collection. Collected data were analyzed by the statistical software IBM SPSS 25. Results: This study shows that the majority (68%) of patients belonged to the age group of 21-30 years. The mean age was 26.43±7.77 years. Regarding sex, 56% were females and 44% were males with a male-female ratio of 1.3:1. 52% of patients had a duration of lesion up to 1 year, 22% of patients had 1-2 years and 26% of patients had >2 years. The most common site of keloid was the chest (38%), then face (32%), upper extremity (16%), shoulder (6%), back (4%). The most common presenting symptoms were pruritis (56%), then 38% were cosmetic disfigurement, 32% were skin discoloration, 28% were pain and 18% were restriction of movement. Trauma was the commonest factor seen in 34% of the patients followed by ear piercing (22%) and infection (20%). Other causes were spontaneous (10%), acne (6%), burns (6%), and post-surgical keloid (2%). 16 had a positive family history of the keloid disease. The majority (70%) had good outcomes followed by excellent outcomes in 22% and 8% had average outcomes. It was observed that most patients (88%) did not have any adverse effects. Only 12% had adverse effects seen as skin ulceration (6%), skin atrophy (4%) and telangiectasia (2%). Conclusion: This study revealed that the combination use of intralesional steroids with 5-fluorouracil in the treatment of keloid seems to offer the balanced benefit of faster and more efficacious response with fewer adverse effects. Treatment has to be individualized and can be combined with one or more modalities to aim for better efficacy and safety. Mediscope 2024;11(1): 41-47

Macrophage phenotype is determinant for fibrosis development in keloid disease

Keloid refers to a fibroproliferative disorder characterized by an accumulation of extracellular matrix (ECM) components at the dermis level, overgrowth beyond initial wound, and formation of tumor-like nodule areas. Treating keloid is still an unmet clinical need and the lack of an efficient therapy is clearly related to limited knowledge about keloid etiology, despite the growing interest of the scientific community in this pathology. In past decades, keloids were often studied in vitro through the sole prism of fibroblasts considered as the major effector of ECM deposition. Nevertheless, development of keloids results from cross-interactions of keloid fibroblasts (KFs) and their surrounding microenvironment, including immune cells such as macrophages. Our study aimed to evaluate the effect of M1 and M2 monocyte-derived macrophages on KFs in vitro. We focused on the effects of the macrophage secretome on fibrosis-related criteria in KFs, including proliferation, migration, differentiation, and ECM synthesis. First, we demonstrated that M2-like macrophages enhanced the fibrogenic profile of KFs in culture. Then, we surprisingly founded that M1-like macrophages can have an anti-fibrogenic effect on KFs, even in a pro-fibrotic environment. These results demonstrate, for the first time, that M1 and M2 macrophage subsets differentially impact the fibrotic fate of KFs in vitro, and suggest that restoring the M1/M2 balance to favor M1 in keloids could be an efficient therapeutic lever to prevent or treat keloid fibrosis.

Identification of inflammation-related biomarkers in keloids.

The relationship between inflammation-related genes (IRGs) and keloid disease (KD) is currently unclear. The aim of this study was to identify a new set of inflammation-related biomarkers in KD. GSE145725 and GSE7890 datasets were used in this study. A list of 3026 IRGs was obtained from the Molecular Signatures Database. Differentially expressed inflammation-related genes (DEGs) were obtained by taking the intersection of DEGs between KD and control samples and the list of IRGs. Candidate genes were selected using least absolute shrinkage and selection operator (LASSO) regression analysis. Candidate genes with consistent expression differences between KD and control in both GSE145725 and GSE7890 datasets were screened as biomarkers. An alignment diagram was constructed and validated, and in silico immune infiltration analysis and drug prediction were performed. Finally, RT-qPCR was performed on KD samples to analyze the expression of the identified biomarkers. A total of 889 DEGs were identified from the GSE145725 dataset, 169 of which were IRGs. Three candidate genes (TRIM32, LPAR1 and FOXF1) were identified by the LASSO regression analysis, and expression validation analysis suggested that FOXF1 and LPAR1 were down-regulated in KD samples and TRIM32 was up-regulated. All three candidate genes had consistent changes in expression in both the GSE145725 and GSE7890 datasets. An alignment diagram was constructed to predict KD. Effector memory CD4 T cells, T follicular helper cell, Myeloid derived suppressor cell, activated dendritic cell, Immature dendritic cell and Monocyte were differentially expressed between the KD and control group. Sixty-seven compounds that may act on FOXF1, 108 compounds that may act on LPAR1 and 56 compounds that may act on TRIM32 were predicted. Finally, RT-qPCR showed that the expression of LPAR1 was significantly lower in KD samples compared to normal samples whereas TRIM32 was significantly higher, while there was no difference in the expression of FOXF1. This study provides a new perspective to study the relationship between IRGs and KD.

Insights into How Plant-Derived Extracts and Compounds Can Help in the Prevention and Treatment of Keloid Disease: Established and Emerging Therapeutic Targets.

Keloid is a disease in which fibroblasts abnormally proliferate and synthesize excessive amounts of extracellular matrix, including collagen and fibronectin, during the healing process of skin wounds, causing larger scars that exceed the boundaries of the original wound. Currently, surgical excision, cryotherapy, radiation, laser treatment, photodynamic therapy, pressure therapy, silicone gel sheeting, and pharmacotherapy are used alone or in combinations to treat this disease, but the outcomes are usually unsatisfactory. The purpose of this review is to examine whether natural products can help treat keloid disease. I introduce well-established therapeutic targets for this disease and various other emerging therapeutic targets that have been proposed based on the phenotypic difference between keloid-derived fibroblasts (KFs) and normal epidermal fibroblasts (NFs). We then present recent studies on the biological effects of various plant-derived extracts and compounds on KFs and NFs. Associated ex vivo, in vivo, and clinical studies are also presented. Finally, we discuss the mechanisms of action of the plant-derived extracts and compounds, the pros and cons, and the future tasks for natural product-based therapy for keloid disease, as compared with existing other therapies. Extracts of Astragalus membranaceus, Salvia miltiorrhiza, Aneilema keisak, Galla Chinensis, Lycium chinense, Physalis angulate, Allium sepa, and Camellia sinensis appear to modulate cell proliferation, migration, and/or extracellular matrix (ECM) production in KFs, supporting their therapeutic potential. Various phenolic compounds, terpenoids, alkaloids, and other plant-derived compounds could modulate different cell signaling pathways associated with the pathogenesis of keloids. For now, many studies are limited to in vitro experiments; additional research and development are needed to proceed to clinical trials. Many emerging therapeutic targets could accelerate the discovery of plant-derived substances for the prevention and treatment of keloid disease. I hope that this review will bridge past, present, and future research on this subject and provide insight into new therapeutic targets and pharmaceuticals, aiming for effective keloid treatment.

Artificial keloid skin models: understanding the pathophysiological mechanisms and application in therapeutic studies.

Keloid is a type of scar formed by the overexpression of extracellular matrix substances from fibroblasts following inflammation after trauma. The existing keloid treatment methods include drug injection, surgical intervention, light exposure, cryotherapy, etc. However, these methods have limitations such as recurrence, low treatment efficacy, and side effects. Consequently, studies are being conducted on the treatment of keloids from the perspective of inflammatory mechanisms. In this study, keloid models are created to understand inflammatory mechanisms and explore treatment methods to address them. While previous studies have used animal models with gene mutations, chemical treatments, and keloid tissue transplantation, there are limitations in fully reproducing the characteristics of keloids unique to humans, and ethical issues related to animal welfare pose additional challenges. Consequently, studies are underway to create in vitro artificial skin models to simulate keloid disease and apply them to the development of treatments for skin diseases. In particular, herein, scaffold technologies that implement three-dimensional (3D) full-thickness keloid models are introduced to enhance mechanical properties as well as biological properties of tissues, such as cell proliferation, differentiation, and cellular interactions. It is anticipated that applying these technologies to the production of artificial skin for keloid simulation could contribute to the development of inflammatory keloid treatment techniques in the future.

Multi-omics analyses reveal bacteria and catalase associated with keloid disease

The pathology of keloid and especially the roles of bacteria on it were not well understood. In this study, multi-omics analyses including microbiome, metaproteomics, metabolomic, single-cell transcriptome and cell-derived xenograft (CDX) mice model were used to explore the roles of bacteria on keloid disease. We found that the types of bacteria are significantly different between keloid and healthy skin. The 16S rRNA sequencing and metaproteomics showed that more catalase (CAT) negative bacteria, Clostridium and Roseburia existed in keloid compared with the adjacent healthy skin. In addition, protein mass spectrometry shows that CAT is one of the differentially expressed proteins (DEPs). Overexpression of CAT inhibited the proliferation, migration and invasion of keloid fibroblasts, and these characteristics were opposite when CAT was knocked down. Furthermore, the CDX model showed that Clostridium butyricum promote the growth of patient's keloid fibroblasts in BALB/c female nude mice, while CAT positive bacteria Bacillus subtilis inhibited it. Single-cell RNA sequencing verified that oxidative stress was up-regulated and CAT was down-regulated in mesenchymal-like fibroblasts of keloid. In conclusion, our findings suggest that bacteria and CAT contribute to keloid disease. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Silibinin Downregulates Types I and III Collagen Expression via Suppression of the mTOR Signaling Pathway.

Keloid scars are fibro-proliferative conditions characterized by abnormal fibroblast proliferation and excessive extracellular matrix deposition. The mammalian target of the rapamycin (mTOR) pathway has emerged as a potential therapeutic target in keloid disease. Silibinin, a natural flavonoid isolated from the seeds and fruits of the milk thistle, is known to inhibit the mTOR signaling pathway in human cervical and hepatoma cancer cells. However, the mechanisms underlying this inhibitory effect are not fully understood. This in vitro study investigated the effects of silibinin on collagen expression in normal human dermal and keloid-derived fibroblasts. We evaluated the effects of silibinin on the expressions of collagen types I and III and assessed its effects on the suppression of the mTOR signaling pathway. Our findings confirmed elevated mTOR phosphorylation levels in keloid scars compared to normal tissue specimens. Silibinin treatment significantly reduced collagen I and III expressions in normal human dermal and keloid-derived fibroblasts. These effects were accompanied by the suppression of the mTOR signaling pathway. Our findings suggest the potential of silibinin as a promising therapeutic agent for preventing and treating keloid scars. Further studies are warranted to explore the clinical application of silibinin in scar management.

Keloid disease and management difficulties

Keloids are benign skin tumor, they can be disabling. We report a case of a 41-year-old-man who suffered for multiple keloids and was treated successfully with surgery and brachytherapy.

Do Mesenchymal Stem Cells Influence Keloid Recurrence?

Mesenchymal stem cells (MSCs) have been postulated by a number of authors to be the precursor cells of fibroblasts and myofibroblasts in keloids. They have been seen as a regenerative pool that ensures a steady supply of cells. The objective of our study was to determine MSCs in keloids and normal skin as a determinant of keloid recurrence. This was a longitudinal prospective study in which patients with keloid excisions of their specimens analyzed for MSC. A control group of patients matched for age, sex, and body-mass index (BMI) with no history of keloids admitted for elective surgical procedures had their skin samples taken and also analyzed for MSCs. Data collected were analyzed and compared using Student's t, x 2, and Fisher's exact t tests. A total of 61 patients with keloids and a control group of 32 patients were recruited. The male:female ratio was 1:2 and mean age 29.5 and 29.7 years for keloids and controls, respectively. Patients with recurrent keloids had a mean density of 841.4 MSCs/g compared to 578 MSCs/g of tissue for those with no recurrence and 580 MSCs/g for patients with normal skin. Recurrent keloids had a significantly higher percentage of MSCs than those without. Keloids compared to normal skin had a higher percentage of MSCs, with recurrent keloids demonstrating an even higher count, a possible indicator that MSCs might correlate with severity of keloid disease and recurrence.

Targeting the Akt/PI3K/mTOR signaling pathway for complete eradication of keloid disease by sunitinib

Keloid disease is a nodular lesion, tumor-like but not cancerous, and characterized of excessive proliferation of fibroblasts and deposition of extracellular matrix (ECM) components. This condition often causes itching, pain and cosmetic disfigurement, significantly reducing patient quality of life. To date, no universally effective therapies are available, possibly due to inadequate understanding of keloid pathogenesis. As an oral small-molecule inhibitor of certain tyrosine kinase receptors, sunitinib has shown significant therapeutic effects in renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). However, it has never been tested if keloid therapy can be effective for the management of keloids. This study thus aims to explore the potential of sunitinib for keloid treatment. Keloid-derived fibroblasts (KFs) were successfully isolated and demonstrated proliferative advantage to normal skin-derived fibroblasts (NFs). Additionally, sunitinib showed specific cytotoxicity and inhibition of invasion, and induced cell cycle arrest and significant apoptosis in KFs. These effects were accompanied by complete suppression of ECM component expression, including collagen types 1 and 3, upregulation of autophagy-associated LC3B and significant suppression of the Akt/PI3K/mTOR pathway. Moreover, a keloid explant culture model was successfully established and used to test the therapeutic efficacy of sunitinib on keloid formation in nude mice. Sunitinib was found to induce complete regression of keloid explant fragments in nude mice, showing significantly higher therapeutic efficacy than the most commonly used intralesional drug triamcinolone acetonide (TAC). These data suggest that sunitinib effectively inhibits keloid development through suppression of the Akt/PI3K/mTOR pathway and thus can be potentially developed as a monotherapy or combination therapy for the effective treatment of keloid disease.

IL-17 Induces Autophagy Dysfunction to Promote Inflammatory Cell Death and Fibrosis in Keloid Fibroblasts via the STAT3 and HIF-1α Dependent Signaling Pathways.

Keloid is an abnormal fibrotic disease after cutaneous injury characterized by exaggerated scar tissue formation, which often extends beyond the boundaries of the original wound. Although chronic inflammation is known to be associated with the excessive inflammation in keloid tissue, there are few studies on the role of autophagy in the pathogenesis of keloid. In this study, we evaluated the pattern of autophagy in keloid fibroblasts (KF) and normal fibroblasts (NF). Expression of HIF-1α, STAT3 and autophagic flux markers were evaluated in KF and NF. Defective autophagy caused by IL-17 was evaluated, and the relationship between defective autophagy and necroptosis was also examined. The expression of IL-17, HIF-1α and STAT3 was significantly increased in keloid tissue, and autophagosome-to autophagolysosome conversion was defective in KF. IL-17 treatment significantly elevated the expression of STAT3 and HIF-1α in NF and caused defective autophagy, which was reversed by HIF-1α inhibitor. In addition, the defective autophagy was associated with the increased necroptosis and fibrosis. In keloid tissue, the elevated necroptosis marker was confirmed, and with the HIF-1α inhibitor, the defective autophagy, necroptosis and fibrosis was decreased in KF. In conclusion, autophagy was defective in keloid tissue, which was associated with increased necroptosis and fibrosis. The IL-17-STAT3-HIF-1α axis was involved in defective autophagy in KF, and this suggests that targeting the axis could alleviate chronic inflammation in keloid disease.

Detection and analysis of long noncoding RNA expression profiles related to epithelial–mesenchymal transition in keloids

BackgroundThe role of epithelial-mesenchymal transition (EMT) in the pathogenesis of keloids is currently raising increasing attention. Long noncoding RNAs (lncRNAs) govern a variety of biological processes, such as EMT, and their dysregulation is involved in many diseases including keloid disease. The aim of this study was to identify differentially expressed EMT-related lncRNAs in keloid tissues versus normal tissues and to interpret their functions.ResultsEleven lncRNAs and 16 mRNAs associated with EMT were identified to have differential expression between keloid and normal skin tissues (fold change > 1.5, P < 0.05). Gene Ontology (GO) analysis showed that these differentially expressed mRNAs functioned in the extracellular matrix, protein binding, the positive regulation of cellular processes, the Set1C/COMPASS complex and histone acetyltransferase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that these mRNAs are involved in pathways in cancer. The lncRNA, XLOC_000587 may promote cell proliferation and migration by enhancing the expression of ENAH, while AF268386 may facilitate the invasive growth of keloids by upregulating DDR2.ConclusionsWe characterized the differential expression profiles of EMT-related lncRNAs and mRNAs in keloids, which may contribute to preventing the occurrence and development of keloids by targeting the corresponding signaling pathways. These lncRNAs and mRNAs may provide biomarkers for keloid diagnosis and serve as potential targets for the treatment of this disease.

Important role of mechanical microenvironment on macrophage dysfunction during keloid pathogenesis.

Keloid is considered as a tumor-like skin disease with multiple aetiologies including immunological factors and mechanical microenvironment. Macrophages are plastic and diverse immune cells that play a critical role in maintaining tissue homeostasis by removing dead cells, debris, pathogens and repairing tissues after inflammation. The imbalance of M1/M2 macrophages and disturbances in macrophage functions can steer the progression of chronic inflammation and lead to the development of pathological fibrosis in keloid disease. Recently, it has been shown that macrophages are sensitive to mechanical signals, especially stretching tension and tissue stiffness, which can determine macrophage polarization and functions. Higher stretching tension is known to be an important pathogenic factor of keloid, and the formation of keloid will lead to an increase in tissue stiffness. As little is known about the underlying reasons of macrophages dysfunction in keloid, an understanding of how the mechanical microenvironment interacting with macrophages and affecting their behaviours may help provide mechanism insights into keloid pathogenesis. We thus hypothesize that the synergistic effect of stretching tension and matrix stiffness may contribute to the major pathophysiological niche attributes of macrophages' in vivo mechanical microenvironment in keloids. These mechanism insights of how macrophages sense and respond to their mechanical microenvironment would propel the development of novel strategies for keloid treatment.

358 The Role of Adipolin in Cutaneous Fibroproliferative Disease

A novel loss of function homozygous mutation in C1QTNF12 (encoding adipolin) was identified in an autosomal recessive pedigree with striking keloid disease. Adipolin is a cytokine with evidence for exerting insulin-sensitising and anti-inflammatory effects. This study aimed to investigate the effect of adipolin on fibroblasts, key effector cells in fibrotic disease. Primary dermal fibroblasts were isolated from the proband (C1QTNF12-null) and wild-type (WT) healthy individuals. The transcriptional profiles of these cells were compared by RNA-sequencing and validated by western blotting.

Suppurative keloids: a complication of severe keloid disease.

Some keloids show cystic cavities that give rise to acute inflammatory flares and oozing. These suppurative keloids (SK) have rarely been systematically studied. We conducted a retrospective cohort study to evaluate SK frequency and its risk factors. We also reviewed microbiological analyses as well as the histological features of removed SKs. Between July 1, 2015, and September 30, 2016, all adult patients attending a specialized keloid clinic were asked to participate. Clinical information and microbiological results were extracted from each patient's file. Histological features were observed and interpreted. In this study, we observed an SK rate of 26% for a mean keloid history of 17.2years. Male gender, African ancestry, and a family history of keloids were significantly associated with suppuration. Microbiological examination revealed commensal skin flora 7/9 (77.8%), Staphylococcusaureus 1/9 (11.1%), and Enterococcusfaecalis 1/9 (11.1%). Suppuration is a common complication of keloids occurring in patients with severe keloid disease and may arise from pilosebaceous occlusion and aseptic inflammation.