The pro-inflammatory environment in recalcitrant diabetic foot wounds.

NewsBot · Nov 14, 2008

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The pro-inflammatory environment in recalcitrant diabetic foot wounds.
Acosta JB, Garcia Del Barco D, Cibrian Vera D, Savigne W, Lopez-Saura P, Guillen Nieto G, Schultz GS.
Int Wound J. 2008 Oct;5(4):530-9.

Lower extremity ulceration is one of the serious and long-term diabetic complications rendering a significant social burden in terms of amputation and quality-of-life reduction. Diabetic patients experience a substantial wound-healing deficit. These lesions are featured by an exaggerated and prolonged inflammatory reaction with a significant impairment in local bacterial invasion control. Experimental and clinical evidences document the deleterious consequences of the wound's pro-inflammatory phenotype for the repair process. From a biochemical standpoint, hyperinflammation favours wound matrix degradation, thus, amplifying a pre-existing granulation tissue productive cells' invasiveness and recruitment deficit. Tumour necrosis factor perpetuates homing of inflammatory cells, triggers pro-apoptotic genes and impairs reepithelialisation. Advanced glycation end-products act in concert with inflammatory mediators and commit fibroblasts and vascular cells to apoptosis, contributing to granulation tissue demise. Therapeutic approaches aimed to downregulate hyperinflammation and/or attenuate glucolipotoxicity may assist in diabetic wound healing by dismantling downstream effectors. These medical interventions are demanded to reduce amputations in an expanding diabetic population.
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admin · Jun 20, 2013

Estimation of lymphocyte apoptosis in patients with chronic, non healing diabetic foot ulcer
Awadhesh Kumar Arya, Sunny Garg, Santosh Kumar, Lalit P Meena, Kamlakar Tripathi.
Int J Med Sci Public Health. 2013; 2(4): -

Background: Lymphocytes play an important role in wound healing and the removal of circulating T lymphocytes inhibits the healing cascade. Decreased stimulation of survival factors and increased levels of dead signals may lead to the malfunction of many cells, including lymphocytes.

Aims & Objective: To explore lymphocytes involvement in wound healing.

Material and Methods: Study participants were divided into three groups: group A, group B and group C (30 participants each). Annexin-V-FITC+CD-3-PE kit were used for the lymphocyte apoptosis estimation in diabetic foot patients by florescent activated cell sorter (FACS).

Results: We find out significantly higher total T cell apoptosis in type 2 diabetes mellitus patients having chronic, non healing diabetic foot ulcer as compared with healthy individuals. CD-3 + Annexin-V-FITC positive lymphocytes were statistically significant in group C (P<0.01) and group B (P<0.001) when compared from group A.

Conclusion: This study suggests the importance of T-lymphocytes in wound healing. From the present study we can suggest diabetic patients to maintain their immune system for the normal wound healing.
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NewsBot · May 30, 2020

Lack of lymphocytes impairs macrophage polarization and angiogenesis in diabetic wound healing
Patricia M.Seraphimab et al
Life Sciences 16 May 2020, 117813

AIMS: This study aimed to investigate the effect of lymphocytes in wound healing and the underlying mechanisms, in diabetic and non-diabetic mice, using Balb/c recombination activating gene (Rag)-2 and interleukin 2 receptor gamma (IL-2Rγ) double knockout (KO) (RAG2−/− IL-2Rγ−/−) mice. MAIN METHODS: Wound healing in vivo was performed in control and STZ-induced diabetic mice, in both KO and WT mice. Inflammation and ROS production were evaluated by immunofluorescence microscopy analysis, antioxidant enzymes and angiogenesis were evaluated by RT-qPCR and immunofluorescence microscopy analysis, and wound closure kinetics evolution was evaluated by measurement of acetate tracing of the wound area. KEY FINDINGS: Wound closure was significantly delayed in KO mice, where the M1/M2 macrophage ratio and basal ROS levels were significantly increased, while antioxidant defenses and angiogenesis were significantly decreased. Moreover, the expected increase in matrix metallopeptidase (MMP)-9 protein levels in diabetic conditions was not observed in KO mice, suggesting that the mechanisms leading to the increase in MMP-9 observed in diabetic wounds may in part be lymphocyte-dependent. SIGNIFICANCE: Our results indicate that lack of lymphocytes compromises wound healing independent of diabetes. The lack of these cells, even in non-diabetic mice, mimics the phenotype observed in wounds under diabetic conditions. Moreover, the combination of diabetes and the lack of lymphocytes, further impair the wound healing conditions, indicating that when the innate regulatory function is lost in these KO mice, excessive M1 polarization, poor angiogenesis and impaired wound healing are worsen.
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NewsBot · Jun 9, 2021

Macrophage Polarization and Diabetic Wound Healing
Amanda E Louiselle et al
Transl Res. 2021 Jun 2;S1931-5244(21)00124-9

Diabetes mellitus is a costly disease and nearly one-third of these costs are attributed to management of diabetic foot disease including chronic, non-healing, diabetic foot ulcers. Therefore, much effort has been placed into understanding the pathogenesis of diabetic wounds and novel therapeutics. A relatively new area of interest has been macrophage polarization and its role in diabetic wound healing. Diabetic wounds show dysregulated and persistent M1 (pro-inflammatory) macrophage polarization whereas normal wounds will display a transition to M2 (pro-healing) macrophages around day three after wounding. We reviewed factors known to affect macrophage polarization, mostly focused on those that contribute to M2 macrophage polarization, and potential treatments that at least in part target macrophage polarization in the diabetic wound bed. Much of the work has been aimed at reducing hyperglycemia and encouraging pro-inflammatory cytokine neutralization or decreased expression given this has a significant role in producing M1 macrophages. Treatment of diabetic wounds will likely require a multi-modal approach including management of underlying diabetes and control of hyperglycemia, topical therapeutics, and prevention of secondary infection and inflammation.
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NewsBot · Aug 15, 2021

MiR-195-5p and miR-205-5p in extracellular vesicles isolated from diabetic foot ulcer wound fluid decrease angiogenesis by inhibiting VEGFA expression.
Liu J et al
Aging, 09 Aug 2021, 13

Diabetic foot ulcers are recalcitrant to healing, and poor angiogenesis is considered as the main contributing factor. We aimed to explore the effect of extracellular vesicles (EVs) derived from wound fluids on new vessel formation in diabetic foot ulcers. EVs were isolated from wound fluids of diabetic foot ulcers (DF-EVs). The inhibitory effect of DF-EVs on human umbilical vein endothelial cells (HUVECs) and wound healing was tested. To elucidate the potential mechanism of these effects, we screened the differentially expressed microRNAs (miRNAs) in DF-EVs via microarray analysis and verified the upregulation of miR-195-5p and miR-205-5p in DF-EVs via quantitative real-time polymerase chain reaction (qRT-PCR). Further dual-luciferase reporter assays and overexpression experiments proved these two miRNAs inhibited the expression of vascular endothelial growth factor A (VEGFA) directly to the 3' untranslated region (UTR) of VEGFA and, in turn, promoted an inhibitory effect of DF-EVs on angiogenesis and wound healing in patients with diabetic foot ulcers. Our study shows EVs in the wound fluids of diabetic foot ulcer lesions carrying antiangiogenic miR-195-5p and miR-205-5p negatively regulated angiogenesis and wound healing in patients with diabetic foot.
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NewsBot · Nov 9, 2021

FOXM1 accelerates wound healing in diabetic foot ulcer by inducing M2 macrophage polarization through a mechanism involving SEMA3C/NRP2/Hedgehog signaling
YangYang et al
Diabetes Research and Clinical Practice; 3 November 2021, 109121

Aims
The diabetic wound environment is accompanied with prolonged inflammation leading to impaired wound healing in diabetic foot ulcer (DFU). Our study illustrated the molecular mechanisms by which Forkhead box M1 (FOXM1) enhanced M2 polarization and wound healing of DFU.

Methods
Diabetes was modeled in vivo by streptozotocin injection in rats and in vitro by exposure to high glucose in human dermal fibroblasts (HDF). Macrophages were exposed to IL-4 to induce M2 phenotype polarization. Ectopic expression or knockdown of FOXM1 was performed to observe collagen deposition, angiogenesis, the proliferation and migration of HDF, as well as macrophage polarization.

Results
FOXM1 was lowly expressed in the wound tissue of DFU rats. In vitro experiments showed that silencing FOXM1 reversed the M2 polarization-induced promotion of HDF proliferation and migration. We further found that FOXM1 bound to the promoter region of SEMA3C to elevate its expression, and SEMA3C upregulated NRP2 and activated the Hedgehog signaling pathway. Silencing of SMO, a signal transducer in the Hedgehog pathway, negated the promoting effect of FOXM1 overexpression in M2 polarization and HDF proliferation.

Conclusions
Thus, our results suggest that targeting transcription factor FOXM1 may provide a therapeutic target for promoting wound healing in DFU.
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NewsBot · Jan 26, 2022

The role of CXCL8 in chronic nonhealing diabetic foot ulcers and phenotypic changes in fibroblasts: a molecular perspective
Vikrant Rai, Rebecca Moellmer & Devendra K. Agrawal
Molecular Biology Reports (2022)

Introduction
A persistent inflammation is perpetuated by infiltrating immune cells and cytokines secreted from these immune cells. Additionally, apoptotic keratinocytes and adipocytes in diabetes causes diabetic foot ulcer (DFU) to arrest in an inflammatory phase without progressing to the resolution phase. This leads to a nonhealing DFU and, despite advanced treatments consisting of wound debridement, off-loading the ulcer of necrotic tissue, wound dressings to keep it moist and control exudate, medication, and preventing infection, DFUs remain a clinical problem. Nonhealing DFUs pose not only an economic burden but also increased morbidity and mortality in the form of psychological stress with and increased chance of amputation, and even death. Thus, investigating the complicated underlying molecular mechanism responsible for nonhealing patterns and designing better therapeutics is warranted. This review article focuses on the role of IL-8-mediated persistent inflammation and phenotypic change of fibroblasts due to this inflammatory cascade. We have discussed various sources of interleukin (IL)-8 secretion and the possible association of IL8-fibroblast plasticity as a cause of nonhealing DFUs.

Material and methods
A literature search on PubMed, Google Scholar, and PMC was done including the terms diabetic foot ulcer, diabetes, diabetic ulcer, chronic inflammation, interleukin 8, diabetic wound, and nonhealing diabetic foot ulcers. The articles in the English language and published in last 10 years were selected. From the pool of these, the articles describing the relationship between IL-8 and nonhealing diabetic foot ulcer and diabetic ulcer were used sorted out and used for this review article following PRISMA guidelines.

Conclusion
Increased infiltration of inflammatory immune cells, secretion of pro-inflammatory cytokines, altered keratinocyte-fibroblast function, and phenotypic changes of fibroblasts in DFUs seem to be critical to the nonhealing of DFUs. Thus, inhibiting IL-8 secretion and downstream signaling seems to be a goal of potential therapeutics.
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NewsBot · May 31, 2022

CHARACTERISTICS OF IMMUNOREACTIVITY IN PATIENTS WITH VARIOUS
FORMS OF DIABETIC FOOT ULCER
Vyacheslav Mykhaylichenko et al
Archiv EuroMedica. 2022. 12; 3: e1

The article presents a comparative assessment of the levels of cytokines that regulate the differentiation of various macrophage phenotypes,
as well as immunological responses in patients with diabetes. We examined and treated 245 patients who were allocated to two groups. The
first group comprised neuropathic patients (comparison subgroup 1A without DFU, n=30 and subgroup 1B with DFU, n=80). The second
group included patients with neuroischemic type 2 diabetes (comparison subgroup 2A without DFU, n=35 and subgroup 2B with DFU,
n=100). As an indicator of hyperglycemia, the glycated hemoglobin level (HbA1c) was used, which was determined on the DCA 2000 device
by the method of latex immunoagglutination inhibition using the “Hemoglobin A1c Reagent kit”. The concentration of cytokines TNF-α, IFNγ, IL-6, and OPG in blood serum was determined on the first day of hospitalization before surgery using enzyme immunoassay test systems
(OOO “Cytokine”, St. Petersburg) in accordance with the manufacturer's instructions. An imbalance of cytokines was revealed, indicating a
shift in immunomodulatory responses, aggravation of metabolic and vascular disorders in tissues, accompanied by an inadequate course of
the inflammatory and reparative process and the formation of a diabetic foot ulcer.
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NewsBot · Dec 18, 2022

Role of fibroblast plasticity and heterogeneity in modulating angiogenesis and healing in the diabetic foot ulcer
Vikrant Rai et al
Mol Biol Rep. 2022 Dec 17

Chronic diabetic foot ulcers (DFUs) are an important clinical issue faced by clinicians despite the advanced treatment strategies consisting of wound debridement, off-loading, medication, wound dressings, and keeping the ulcer clean. Non-healing DFUs are associated with the risk of amputation, increased morbidity and mortality, and economic stress. Neo-angiogenesis and granulation tissue formation are necessary for physiological DFU healing and acute inflammation play a key role in healing. However, chronic inflammation in association with diabetic complications holds the ulcer in the inflammatory phase without progressing to the resolution phase contributing to non-healing. Fibroblasts acquiring myofibroblasts phenotype contribute to granulation tissue formation and angiogenesis. However, recent studies suggest the presence of five subtypes of fibroblast population and of changing density in non-healing DFUs. Further, the association of fibroblast plasticity and heterogeneity with wound healing suggests that the switch in fibroblast phenotype may affect wound healing. The fibroblast phenotype shift and altered function may be due to the presence of chronic inflammation or a diabetic wound microenvironment. This review focuses on the role of fibroblast plasticity and heterogeneity, the effect of hyperglycemia and inflammatory cytokines on fibroblasts, and the interaction of fibroblasts with other cells in diabetic wound microenvironment in the perspective of DFU healing. Next, we summarize secretory, angiogenic, and angiostatic phenotypes of fibroblast which have been discussed in other organ systems but not in relation to DFUs followed by the perspective on the role of their phenotypes in promoting angiogenesis in DFUs.
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NewsBot · Feb 21, 2023

Transcriptional heterogeneity in diabetic foot wounds
Teresa Sandoval-Schaefer, Quan Phan, Biraja Dash, Alexandre Prassinos, Kaiti Duan, Michael I Gazes, Steven D. Vyce, Henry C. Hsai, Ryan Driskell, View ORCID ProfileValerie Horsley
This article is a preprint and has not been certified by peer review

Wound repair requires the coordination of multiple cell types including immune cells and tissue resident cells to coordinate healing and return of tissue function. Diabetic foot ulceration is a type of chronic wound that impacts over 4 million patients in the US and over 7 million worldwide (Edmonds et al., 2021). Yet, the cellular and molecular mechanisms that go awry in these wounds are not fully understood. Here, by profiling chronic foot ulcers from non-diabetic (NDFUs) and diabetic (DFUs) patients using single-cell RNA sequencing, we find that DFUs display transcription changes that implicate reduced keratinocyte differentiation, altered fibroblast function and lineages, and defects in macrophage metabolism, inflammation, and ECM production compared to NDFUs. Furthermore, analysis of cellular interactions reveals major alterations in several signaling pathways that are altered in DFUs. These data provide a view of the mechanisms by which diabetes alters healing of foot ulcers and may provide therapeutic avenues for DFU treatments.
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NewsBot · Nov 13, 2023

Exploration of the common pathogenic link between COVID-19 and diabetic foot ulcers: An in silico approach
Xueyao Cai et al
Health Sci Rep. 2023 Nov 5;6(11)

Background and aims: The Coronavirus Disease-19 (COVID-19) is posing an ongoing threat to human health. Patients of diabetic foot ulcer (DFU) are susceptible to COVID-19-induced adverse outcomes. Nevertheless, investigations into their mutual molecular mechanisms have been limited to date. In the present work, we tried to uncover the shared pathogenesis and regulatory gene targets of COVID-19 and DFU.

Methods: In this study, we chose GSE161281 as the COVID-19 data set, which contained severe acute respiratory syndrome coronavirus 2 infected human induced embryonic stem cell-derived peripheral neurons (n = 2) with uninfected controls (n = 2). The GSE134431 designated as the DFU data set, comprising full-thickness DFU (n = 13) and diabetic foot skin (n = 8) samples from diabetic patients. The differential expressed genes (DEGs) were identified from GSE161281 and GSE134431, and the common DEGs between COVID-19 and DFU were extracted. Multifactor regulatory network and co-expression network of the common DEGs were analyzed, along with candidate drug prediction.

Results: Altogether, six common DEGs (dickkopf-related protein 1 [DKK1], serine proteinase inhibitor A3 [SERPINA3], ras homolog family member D [RHOD], myelin protein zero like 3 [MPZL3], Claudin-11 [CLDN11], and epidermal growth factor receptor pathway substrate 8-like 1 [EPS8L1]) were found between COVID-19 and DFU. Functional analyses indicated that pathways of apoptotic and Wnt signaling may contribute to progression of COVID-19. Gene co-expression network implied the shared pathways of immune regulation and cytokine response participated collectively in the development of DFU and COVID-19. A multifactor regulatory network was constructed integrating the corresponding microRNAs (miRNAs) and transcription factors. Additionally, we proposed potential drug objects for the combined therapy.

Conclusion: Our study revealed the shared molecular mechanisms underlying COVID-19 and DFU. The identified pivotal targets and common pathways can provide new perspectives for further research and assist the development of management strategies in patients of DFU complicated with COVID-19
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NewsBot · Feb 26, 2024

Macrophages regulate healing-associated fibroblasts in diabetic wound
Yu Xiao et al
Mol Biol Rep. 2024 Jan 25;51(1):203

Background: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages.

Methods and results: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1β (IL1β), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice.

Conclusions: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.
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