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FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers

ABSTRACT: Diabetic foot ulcers (DFU) are a serious complication of diabetes mellitus and associated with reduced quality of life and high mortality rate. DFUs are characterized by a deregulated immune response with decreased neutrophils due to loss of the transcription factor, FOXM1. Diabetes primes neutrophils to form neutrophil extracellular traps (NETs), contributing to tissue damage and impaired healing. However, the role of FOXM1 in priming diabetic neutrophils to undergo NET formation remains unknown. Here, we found that FOXM1 regulates reactive oxygen species (ROS) levels in neutrophils. Inhibition of FOXM1 results in increased ROS leading to NET formation. Next generation sequencing revealed TREM1 promoted the recruitment of FOXM1+ neutrophils and reversed effects of diabetes and promoted wound healing in vivo. Moreover, we found TREM1 expression correlated with clinical healing outcomes of DFUs, indicating TREM1 may serve as a useful biomarker or a potential therapeutic target. Our findings highlight the clinical relevance of TREM1, and indicates FOXM1 pathway as a novel regulator of NET formation during diabetic wound healing, revealing new therapeutic strategies to promote healing in DFUs.

SUBMITTER: Dr. Andrew, P. Sawaya

PROVIDER: S-SCDT-EMBOR-2021-54558V1 | biostudies-other |

REPOSITORIES: biostudies-other

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FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers.

Project description:Diabetic foot ulcers (DFU) are a serious complication of diabetes mellitus and associated with reduced quality of life and high mortality rate. DFUs are characterized by a deregulated immune response with decreased neutrophils due to loss of the transcription factor, FOXM1. Diabetes primes neutrophils to form neutrophil extracellular traps (NETs), contributing to tissue damage and impaired healing. However, the role of FOXM1 in priming diabetic neutrophils to undergo NET formation remains unknown. Here, we found that FOXM1 regulates reactive oxygen species (ROS) levels in neutrophils and inhibition of FOXM1 results in increased ROS leading to NET formation. Next generation sequencing revealed that TREM1 promoted the recruitment of FOXM1+ neutrophils and reversed effects of diabetes and promoted wound healing in vivo. Moreover, we found that TREM1 expression correlated with clinical healing outcomes of DFUs, indicating TREM1 may serve as a useful biomarker or a potential therapeutic target. Our findings highlight the clinical relevance of TREM1, and indicates FOXM1 pathway as a novel regulator of NET formation during diabetic wound healing, revealing new therapeutic strategies to promote healing in DFUs.

| S-EPMC9346470 | biostudies-literature

Association of MCP-1 rs1024611 polymorphism with diabetic foot ulcers.

Project description:Monocyte chemotactant protein-1 (MCP-1), a pro-inflammatory cytokine, plays an important role in inflammatory process. In present study, we evaluated the association of MCP-1 gene rs1024611 polymorphism with risk and clinical characteristics of diabetic foot ulcers (DFUs).This study recruited 116 patients with DFUs, 135 patients with diabetes mellitus (DM) without complications (non-DFU), and 149 healthy controls (HCs). MCP-1 gene rs1024611 polymorphism was genotyped by direct sequencing. The expression of MCP-1 was analyzed using quantitative real-time polymerase chain reaction. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assume the association strength.Individuals with rs1024611 AG and GG genotypes exhibited significantly higher susceptibility to DFUs, in the comparison with HCs (AG vs AA, OR = 2.364, 95% CI = 1.021-5.470; GG vs AA, OR = 2.686, 95% CI = 1.154-6.255). Meanwhile, G allele was associated with increased DFUs susceptibility (OR = 1.457, 95% CI = 1.014-2.093). Besides, rs1024611 SNP was slightly correlated with increased DFUs susceptibility in patients with DM. GG genotype of rs1024611 was significantly correlated with higher epidermal thickness and lower dermis thickness in patients with DFUs (P < .01). Patients with DFU exhibited upregulation of MCP-1 mRNA, and GG genotype was correlated with enhanced MCP-1 expression in DFU and non-DFU groups.Rs1024611 polymorphism was significantly associated with MCP-1 expression and individual susceptibility to DFUs.

| S-EPMC6076038 | biostudies-literature

Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers

Project description:Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. In order to identify systemic and local factors associated with DFU healing, we examined the cellular landscape of DFUs by single-cell RNA-seq analysis of foot and forearm skin specimens, as well as PBMC samples, from 10 non-diabetic subjects, and 17 diabetic patients, 11 with, and 6 without DFU. Our analysis shows enrichment of a unique inflammatory fibroblast population in DFU patients with healing wounds. The patients with healing DFUs also depicted enrichment of macrophages with M1 polarization, as opposed to more M2 macrophages in non-healing wounds. These findings were verified using Immunohistochemistry and Spatial Transcriptomics.

2021-11-01 | GSE165816 | GEO

Association of Hemoglobin A1c and Wound Healing in Diabetic Foot Ulcers.

Project description:OBJECTIVE:This study evaluated the association between hemoglobin A1c (A1C) and wound outcomes in patients with diabetic foot ulcers (DFUs). RESEARCH DESIGN AND METHODS:We conducted a retrospective analysis of an ongoing prospective, clinic-based study of patients with DFUs treated at an academic institution during a 4.7-year period. Data from 270 participants and 584 wounds were included in the analysis. Cox proportional hazards regression was used to assess the incidence of wound healing at any follow-up time in relation to categories of baseline A1C and the incidence of long-term (?90 days) wound healing in relation to tertiles of nadir A1C change and mean A1C change from baseline, adjusted for potential confounders. RESULTS:Baseline A1C was not associated with wound healing in univariate or fully adjusted models. Compared with a nadir A1C change from baseline of -0.29 to 0.0 (tertile 2), a nadir A1C change of 0.09 to 2.4 (tertile 3) was positively associated with long-term wound healing in the subset of participants with baseline A1C <7.5% (hazard ratio [HR] 2.07; 95% CI 1.08-4.00), but no association with wound healing was seen with the mean A1C change from baseline in this group. Neither nadir A1C change nor mean A1C change were associated with long-term wound healing in participants with baseline A1C ?7.5%. CONCLUSIONS:There does not appear to be a clinically meaningful association between baseline or prospective A1C and wound healing in patients with DFUs. The paradoxical finding of accelerated wound healing and increase in A1C in participants with better baseline glycemic control requires confirmation in further studies.

| S-EPMC6014539 | biostudies-literature

Co-expression network analysis revealing the key lncRNAs in diabetic foot ulcers.

Project description:Introduction:Diabetic foot ulcers (DFUs) are the most common foot injuries leading to lower extremity amputation in diabetic patients. Recent studies showed that long non-coding RNAs (lncRNAs) played important roles in diverse biological processes. In this study, we focused on identifying differentially expressed long non-coding RNAs (lncRNAs) in DFU. Material and methods:Real-time PCR assay was performed to validate the expression pattern of lncRNAs in DFU. Moreover, co-expression networks were also constructed to identify hub lncRNAs in DFU. Specifically, gene ontology (GO) analysis was first performed to evaluate the potential roles of differentially expressed genes (DEGs) and lncRNAs in DFU. Results:In the present study, we identified 58 up-regulated lncRNAs and 42 down-regulated lncRNAs in DFU samples compared to non-diabetic foot skin samples by analyzing the GSE68186 dataset. Four lncRNAs (FLJ30679, LINC01193, LINC00692, and LINC00641) were observed to be up-regulated in DFU. Furthermore, we found that the down-regulated lncRNA-mediated co-expression network contained 42 lncRNAs and 700 DEGs and the up-regulated lncRNA mediated co-expression network contained 58 lncRNAs and 688 DEGs. Conclusions:Bioinformatics analysis showed that differentially expressed lncRNAs were involved in regulating the ERK1 and ERK2 cascade, secondary alcohol biosynthetic process, centrosome duplication and DNA repair. These results suggested the potential prognostic value of lncRNAs in DFU.

| S-EPMC6764308 | biostudies-literature

Exploration of miRNAs in diabetic foot ulcers of mice

Project description:To investigate the expression of miRNAs in C57 diabetic ulcer mice by Small RNA sequencing

2024-08-31 | GSE275847 | GEO

Update on management of diabetic foot ulcers.

Project description:Diabetic foot ulcers (DFUs) are a serious complication of diabetes that results in significant morbidity and mortality. Mortality rates associated with the development of a DFU are estimated to be 5% in the first 12 months, and 5-year morality rates have been estimated at 42%. The standard practices in DFU management include surgical debridement, dressings to facilitate a moist wound environment and exudate control, wound off-loading, vascular assessment, and infection and glycemic control. These practices are best coordinated by a multidisciplinary diabetic foot wound clinic. Even with this comprehensive approach, there is still room for improvement in DFU outcomes. Several adjuvant therapies have been studied to reduce DFU healing times and amputation rates. We reviewed the rationale and guidelines for current standard of care practices and reviewed the evidence for the efficacy of adjuvant agents. The adjuvant therapies reviewed include the following categories: nonsurgical debridement agents, dressings and topical agents, oxygen therapies, negative pressure wound therapy, acellular bioproducts, human growth factors, energy-based therapies, and systemic therapies. Many of these agents have been found to be beneficial in improving wound healing rates, although a large proportion of the data are small, randomized controlled trials with high risks of bias.

| S-EPMC5793889 | biostudies-other

Growth factors for treating diabetic foot ulcers.

Project description: Not available

| S-EPMC8665376 | biostudies-literature

Spatial transcriptomics of healing and non-healing diabetic foot ulcers

Project description:Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. To better understand the molecular mechanisms and cell types implicated in DFU healing, we used NanoString’s GeoMx Digital Spatial profiling platform on DFU tissue sections and compared gene expression of areas within the same ulcer as well as between patients who in 12 weeks following surgery healed their DFU (Healers, N=2) vs those who did not (Non-Healers, N=2).

2021-10-28 | GSE166120 | GEO

Characterization of Diabetic and Non-Diabetic Foot Ulcers Using Single-Cell RNA-Sequencing

Project description:We examined the feasibility of single cell RNA sequencing (scRNA-seq) analysis to evaluate human chronic wound samples acquired in the clinic, subjected to prolonged cold ischemia time, and processed without FACS sorting. Wound tissue from human diabetic and non-diabetic plantar foot ulcers were evaluated using an optimized 10X Genomics scRNA-seq platform and analyzed using a modified data pipeline designed for low-yield specimens. Cell subtypes were identified informatically and their distributions and transcriptional programs were compared between diabetic and non-diabetic tissue. 139,000 diabetic and non-diabetic wound cells were delivered for 10X capture after either 90 or 180 min of cold ischemia time. cDNA library concentrations were 858.7 and 364.7 pg/µL, respectively, prior to sequencing. Among all barcoded fragments, we found that 83.5% successfully aligned to the human transcriptome and 68% met the minimum cell viability threshold. The average mitochondrial mRNA fraction was 8.5% for diabetic cells and 6.6% for non-diabetic cells, correlating with differences in cold ischemia time. A total of 384 individual cells were of sufficient quality for subsequent analyses; from this cell pool, we identified transcriptionally-distinct cell clusters whose gene expression profiles corresponded to fibroblasts, keratinocytes, neutrophils, monocytes, and endothelial cells. Fibroblast subpopulations with differing fibrotic potentials were identified, and their distributions were found to be altered in diabetic vs. non-diabetic cells.

2023-11-25 | GSE248247 | GEO

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