Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression.

Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1ß were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.

Adaptation of Staphylococcus aureus in a Medium Mimicking a Diabetic Foot Environment.

Staphylococcus aureus is the most prevalent pathogen isolated from diabetic foot infections (DFIs). The purpose of this study was to evaluate its behavior in an in vitro model mimicking the conditions encountered in DFI. Four clinical S. aureus strains were cultivated for 16 weeks in a specific environment based on the wound-like medium biofilm model. The adaptation of isolates was evaluated as follows: by Caenorhabditis elegans model (to evaluate virulence); by quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) (to evaluate expression of the main virulence genes); and by Biofilm Ring test® (to assess the biofilm formation). After 16 weeks, the four S. aureus had adapted their metabolism, with the development of small colony variants and the loss of ß-hemolysin expression. The in vivo nematode model suggested a decrease of virulence, confirmed by qRT-PCRs, showing a significant decrease of expression of the main staphylococcal virulence genes tested, notably the toxin-encoding genes. An increased expression of genes involved in adhesion and biofilm was noted. Our data based on an in vitro model confirm the impact of environment on the adaptation switch of S. aureus to prolonged stress environmental conditions. These results contribute to explore and characterize the virulence of S. aureus in chronic wounds.

Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation.

Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular disease, and cancer. These delays increase a patient's risk for infection and, in severe cases, can result in the formation of chronic, non-healing ulcers (e.g., diabetic foot ulcers, surgical site infections, pressure ulcers and venous leg ulcers). Chronic wounds are very difficult and expensive to treat and there is an urgent need to develop more effective therapeutics that restore healing processes. Sustained innate immune activation and inflammation are common features observed across most chronic wound types. However, the factors driving this activation remain incompletely understood. Emerging evidence suggests that the composition and structure of the wound microbiome may play a central role in driving this dysregulated activation but the cellular and molecular mechanisms underlying these processes require further investigation. In this review, we will discuss the current literature on: 1) how bacterial populations and biofilms contribute to chronic wound formation, 2) the role of bacteria and biofilms in driving dysfunctional innate immune responses in chronic wounds, and 3) therapeutics currently available (or underdevelopment) that target bacteria-innate immune interactions to improve healing. We will also discuss potential issues in studying the complexity of immune-biofilm interactions in chronic wounds and explore future areas of investigation for the field.

Correlation between the platelet-to-lymphocyte ratio and diabetic foot ulcer in patients with type 2 diabetes mellitus.

OBJECTIVE: To investigate the correlation between the platelet-to-lymphocyte ratio (PLR) and diabetic foot ulcer (DFU) in patients with type 2 diabetes mellitus (T2DM). METHOD: From January 2018 to August 2019, 206 patients with T2DM admitted to the Central Hospital of Wuhan, China, were enrolled in this study, including 104 patients with DFU (DFU group) and 102 patients without DFU (T2DM group). During the same period, 90 healthy subjects were randomly screened as normal controls (NC group). The correlation between PLR and DFU in patients with T2DM was explored by comparing the PLR of the subjects in the three groups. RESULTS: The PLRs of the DFU and T2DM groups were higher than that of the NC group, whereas the PLR of the DFU group was higher than that of the T2DM group (p < 0.05). PLR was positively correlated with the Wagner DFU grade (p < 0.001). Based on logistic regression analysis, PLR was found to be an independent risk factor for DFU (OR =1.029, 95% CI: 1.019 ~ 1.039, p < 0.001). The receiver operating characteristic curve analysis of the PLR showed that the area under the curve of the PLR for predicting diabetic foot ulcer was 0.776 (p < 0.001), and the analysis determined that the optimal critical value of the PLR for predicting DFU was 147.6. CONCLUSION: The PLR is significantly elevated in patients with DFU and positively correlated with the Wagner DFU grade, which might be a valuable marker for early diagnosis and assessment of severity of DFU.

miR-19a/b and miR-20a Promote Wound Healing by Regulating the Inflammatory Response of Keratinocytes.

Persistent and impaired inflammation impedes tissue healing and is a characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. In this study, we show that in human wound-edge keratinocytes, the expressions of microRNA (miR)-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, are upregulated during wound repair. However, their levels are lower in chronic ulcers than in acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines and cytokines by keratinocytes. Thus, miR-19a/b and miR-20a being crucial regulators of wound inflammation, the lack thereof may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.

Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing.

Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of "ideal" adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.

An Overview of Ozone Therapy for Treating Foot Ulcers in Patients With Diabetes.

Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes mellitus, which is becoming increasingly prevalent throughout the world, with high mortality and morbidity. Because of the complex pathophysiological processes involved, DFU is difficult to treat effectively with traditional therapies. Ozone therapy, an emerging method, has been reported as potentially beneficial for closure of DFUs and may gradually move to the forefront of clinical practice. Possible mechanisms of action include antioxidant capacity, pathogen inactivation, vascular and endogenous growth factor modulation, and immune system activation. However, some researchers are skeptical about its safety, and clinical trials are lacking. This article reviews the current research and application of ozone therapy for DFUs.

Long Noncoding RNA GAS5 Regulates Macrophage Polarization and Diabetic Wound Healing.

A central feature of diabetic (Db) wounds is the persistence of chronic inflammation, which is partly due to the prolonged presence of proinflammatory (M1) macrophages. Using in vivo and in vitro analyses, we have tested the hypothesis that long noncoding RNA GAS5 is dysregulated in Db wounds. We have assessed the contribution of GAS5 to the M1 macrophage phenotype, as well as the functional consequences of knocking down its expression. We found that expression of GAS5 is increased significantly in Db wounds and in cells isolated from Db wounds. Hyperglycemia induced GAS5 expression in macrophages in vitro. Overexpression of GAS5 in vitro promoted macrophage polarization toward an M1 phenotype by upregulating signal transducer and activator of transcription 1. Of most significance in our judgment, GAS5 loss-of-function enhanced Db wound healing. These data indicate that the relative level of long noncoding RNA GAS5 in wounds plays a key role in the wound healing response. Reductions in the levels of GAS5 in wounds appeared to enhance healing by promoting transition of M1 macrophages to M2 macrophages. Thus, our results suggest that targeting long noncoding RNA GAS5 may provide a therapeutic intervention for correcting impaired Db wound healing.

The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis.

As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.

miR-203 Acts as an Inhibitor for Epithelial-Mesenchymal Transition Process in Diabetic Foot Ulcers via Targeting Interleukin-8.

OBJECTIVES: As a complication of diabetes mellitus (DM), one of the leading causes for death and disability for DM patients is diabetic foot ulcers (DFUs). Epithelial to mesenchymal transition (EMT) plays a critical role in wound healing of DFUs. miR-203 is specifically enriched in keratinocytes and has been shown to target interleukin 8 (IL-8), which acts as an activator for the EMT process. In this study, we explored the interaction between miR-203 and IL-8 in DFU rat models and human keratinocyte cells, underlying the mechanism of miR-203's function in DFUs progression. METHODS: DFU rat models were used to test gene expression in DFU progression. Diabetic keratinocyte cell lines were used to validate in vitro. Wound healing and Transwell assays were applied to evaluate cell migration and invasion abilities. The EMT process was estimated by testing expression of E-cadherin, Vimentin and Slug. The interaction between miR-203 and IL-8 was determined by Luciferase assay. RESULTS: Our results demonstrated that the wound-healing process had been slowed in DFUs, and the advanced glycation end products (AGEs) and the receptor for advanced glycation end products (RAGEs) in wound tissue were of a higher expression than those in normal rat. miR-203 was increased in skin tissues from DFU rat models, while IL-8 was decreased. Through knock-down of miR-203 in AGE-treated keratinocyte cells, it had been shown that the downregulation of miR-203 could promote cell proliferation and migration, and facilitate the EMT process. Meanwhile, Luciferase assay proved that miR-203 could directly target and inhibit IL-8. The repression of IL-8 could rescue the outcomes brought about by miR-203 inhibition. CONCLUSIONS: The upregulation of miR-203 in DFU tissues impaired wound healing by the repress EMT process. Specific knock-down of miR-203 could promote wound healing through the reactivation of its target gene IL-8 and the downstream IL-8/AKT pathway.

Marine Isopod Ceratothoa Oestroides Extract: a Novel Treatment for Diabetic Foot Ulcers? Case Report of an Immunosuppressed Patient.

INTRODUCTION: Diabetic foot ulcer (DFU) is a common lower-extremity complication in patients with diabetes mellitus. A novel DFU treatment is tested by using an ointment containing as healing agent olive oil isopod Ceratothoa oestroidesextract. CASE REPORT: A 58 years old obese man,smoker, with a history of unregulated Type 2 Diabetes Mellitus, peripheral neuropathy and Hodgkin lymphoma was referred to Athens-Greece university hospital Laikon. The patient presented clinically with a lower extremity DFU and peripheral neuropathy with dysesthesia and disturbed sensation of hot and cold. He was treated with an ointment containing C. oestroides extract for five months, without any antimicrobial treatment. Therapy was evaluated by measurement of the transepidermal water loss, skin hydration, photo documentation and planimetry. At each patient's visit, DFU presented a satisfactory healing process. Five months after treatment initiation the patient had complete healing of his DFU. Blood tests after treatment revealed a significant reduction of the levels of the inflammatory markers. Ulcer cultures did not reveal any microbial development neither before nor after treatment. CONCLUSION: The administration of the C. oestroides extract ointment proved to be effective in this case. Although these results should be further investigated, the reported case suggests a novel option for the management of neuropathic diabetic foot ulcers, especially in patients with severe co-morbidities.

Circulatory levels of B-cell activating factor of the TNF family in patients with diabetic foot ulcer: Association with disease progression.

Enhanced and prolonged expression of tumor necrosis factor alpha (TNF-α), a potent pro-inflammatory cytokine is evidenced during the chronic wound healing process of infected diabetic foot ulcer (IDFU). B-cell activating factor (BAFF) is the member of TNF-α family, which implicit in B-cell dysfunction. This study was aimed to evaluate the role of BAFF in diabetic foot ulcer (DFU) patients and to correlate its association with other family of inflammatory cytokines. Circulating levels of BAFF and other cytokines were measured in IDFU (n = 44) and non-IDFU patients (n = 40) using multiplexed bead-based cytokine immunoassay. A stepwise significant increase was observed in both circulatory BAFF and C-reactive protein (CRP) during the disease progression. The area under the receiver operating characteristic curve (AUCROC ) for BAFF was found to be high (0.89; [95% CI: 0.73-1.0]), when compared to CRP (0.68; [95% CI: 0.61-0.76]). Optimum diagnostic cutoff level for BAFF was found to be ≥2.35 pg/mL with 62.0% sensitivity and 85.7% specificity. Further, BAFF levels showed a significant positive correlation with CRP among IDFU patients. With respect to other family cytokines, BAFF levels were positively correlated with TNF-α, interferon family cytokines such as IFN-α2, IL-28A/IFN-λ2, IFN-γ, and IL-10 family cytokines such as IL-19, IL-22, and IL-26 and negatively correlated with IL-6 receptor family such as gp130/sIL-6Rß. Hence, our data suggest that devising therapeutic strategies to reduce the levels of BAFF may contribute in amelioration of IDFU.

Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio are Associated with Lower Extremity Vascular Lesions in Chinese Patients with Type 2 Diabetes.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are inflammatory markers used for prediction of chronic complications of diabetes. Lower extremity arterial disease (LEAD) is one of chronic complications of type 2 diabetes mellitus (T2DM). The correlation between NLR, PLR, and lower extremity vascular lesions was investigated in subjects with T2DM to determine the best predictive marker for LEAD. METHODS: Three hundred thirty-five patients with T2DM (199 males and 136 females; age 54.12 ± 14.07 years) were enrolled. Blood differential counts and anklebrachial index (ABI) were assessed. Patients were divided into the LEAD group (ABI ≤ 0.9, n = 236) and non-LEAD group (ABI > 0.9, n = 99), and NLR and PLR were compared between the two groups. The independent risk factors for LEAD were analyzed using a logistic regression model. Receiver operating characteristic (ROC) curve analysis was used to assess the optimal cutoff values of PLR and NLR for prediction of LEAD. RESULTS: NLR and PLR in the LEAD group were significantly increased compared to non-LEAD group patients. Univariate analyses identified that NLR was positively correlated with age, glycosylated hemoglobin (HbA1c), triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and 2-hours postprandial glucose levels. PLR was positively correlated with age, duration of T2DM, HbA1c, TG, TC, and LDL, but negatively correlated with diastolic blood pressure and fasting C-peptide levels. Binary logistic regression analysis identified that age, total number of white blood cells, PLR, and TC were significant and independent factors of diabetic LEAD. Moreover, ROC curve analysis showed that NLR and PLR were both predictive markers of LEAD in diabetes, and that the area under the PLR curve was larger than NLR. CONCLUSIONS: NLR and PLR are positively correlated with LEAD in diabetes. PLR was superior to NLR as a predictor of LEAD in diabetes.

Macrophage immunomodulation: An indispensable tool to evaluate the performance of wound dressing biomaterials.

A major burden of the healthcare system resides in providing proper medical treatment for all types of chronic wounds, which are usually treated with dressings to induce a faster regeneration. Hence, to reduce healing time and improve the patient's quality of life, it is extremely important to select the most appropriate constituent material for a specific wound dressing. A wide range of wound dressings exist but their mechanisms of action are poorly explored, especially concerning the immunomodulatory effects that occur from the interactions between immune cells and the biomaterial. Tissue-resident and monocyte-derived recruited macrophages are key regulators of wound repair. These phagocytic immune cells exert specific functions during the different stages of wound healing. The recognition of the substantial role of macrophages in the outcome of the wound healing process requires specific understanding of the immunomodulatory effects of commercially available or newly developed wound dressings. For a precise intervention, it is necessary to obtain more knowledge on macrophage polarization in different phases of wound healing in the presence of the dressings. The main purpose of this review is to collect clinical cases in which macrophage immunomodulation was taken into consideration as an indicator of the performances of novel or mainstream wound dressing materials, including those provided with antimicrobial properties.

Immune aging in diabetes and its implications in wound healing.

Immune systems have evolved to recognize and eliminate pathogens and damaged cells. In humans, it is estimated to recognize 109 epitopes and natural selection ensures that clonally expanded cells replace unstimulated cells and overall immune cell numbers remain stationary. But, with age, it faces continuous repertoire restriction and concomitant accumulation of primed cells. Changes shaping the aging immune system have bitter consequences because, as inflammatory responses gain intensity and duration, tissue-damaging immunity and inflammatory disease arise. During inflammation, the glycolytic flux cannot cope with increasing ATP demands, limiting the immune response's extent. In diabetes, higher glucose availability stretches the glycolytic limit, dysregulating proteostasis and increasing T-cell expansion. Long-term hyperglycemia exerts an accumulating effect, leading to higher inflammatory cytokine levels and increased cytotoxic mediator secretion upon infection, a phenomenon known as diabetic chronic inflammation. Here we review the etiology of diabetic chronic inflammation and its consequences on wound healing.

Screening and preliminary validation of T lymphocyte immunoregulation­associated long non­coding RNAs in diabetic foot ulcers.

The present study aimed to investigate the existence of immunoregulation­associated long non­coding (lnc)RNAs mediated by T lymphocytes in the wound surfaces of diabetic foot ulcers (DFUs). The wound skin tissues of patients receiving debridement for trauma or DFUs associated with infection were obtained. Dermatological histological changes were observed by pathological staining, and T lymphocyte subsets and inflammation­associated cytokines were identified. Gene chip technology was used to screen for lncRNAs regulated by immune cells. The wound skin structure in the control group was revealed to be complete, and the inflammatory response was not marked. However, the wound skin structure in the ulcer group was disordered and exhibited a notable inflammatory response. Compared with the control group, expression levels of cluster of differentiation (CD)3 and CD8 in the wound surface tissues of the ulcer group were significantly increased, while the expression levels of interleukin (IL)­1ß, IL­2, IL­10, interferon­Î³ and tumor necrosis factor­α were significantly upregulated. A target regulatory association was identified between downregulated lncRNA­ENST00000411554 and upregulated mitogen­activated protein kinase (MAPK)1 in DFU tissues, and a negative correlation was detected between this RNA and protein. The present results suggested that an immune functional disorder of T lymphocytes may be closely associated with the development of DFUs. Furthermore, activation of the MAPK signal transduction pathway mediated by the lncRNA­ENST00000411554/MAPK1 axis may affect the DFU immune regulatory imbalance.

Tracking Anti-Staphylococcus aureus Antibodies Produced In Vivo and Ex Vivo during Foot Salvage Therapy for Diabetic Foot Infections Reveals Prognostic Insights and Evidence of Diversified Humoral Immunity.

Management of foot salvage therapy (FST) for diabetic foot infections (DFI) is challenging due to the absence of reliable diagnostics to identify the etiologic agent and prognostics to justify aggressive treatments. As Staphylococcus aureus is the most common pathogen associated with DFI, we aimed to develop a multiplex immunoassay of IgG in serum and medium enriched for newly synthesized anti-S. aureus antibodies (MENSA) generated from cultured peripheral blood mononuclear cells of DFI patients undergoing FST. Wound samples were collected from 26 DFI patients to identify the infecting bacterial species via 16S rRNA sequencing. Blood was obtained over 12 weeks of FST to assess anti-S. aureus IgG levels in sera and MENSA. The results showed that 17 out of 26 infections were polymicrobial and 12 were positive for S. aureus While antibody titers in serum and MENSA displayed similar diagnostic potentials to detect S. aureus infection, MENSA showed a 2-fold-greater signal-to-background ratio. Multivariate analyses revealed increases in predictive power of diagnosing S. aureus infections (area under the receiver operating characteristic curve [AUC] > 0.85) only when combining titers against different classes of antigens, suggesting cross-functional antigenic diversity. Anti-S. aureus IgG levels in MENSA decreased with successful FST and rose with reinfection. In contrast, IgG levels in serum remained unchanged throughout the 12-week FST. Collectively, these results demonstrate the applicability of serum and MENSA for diagnosis of S. aureus DFI with increased power by combining functionally distinct titers. We also found that tracking MENSA has prognostic potential to guide clinical decisions during FST.

Frequency of Circulating B1a and B2 B-cell Subsets in Egyptian Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a growing health problem in Egypt. T2DM is recognized as chronic inflammatory disease with involvement of immune cells including B cells. We aimed to determine the frequency of antibody secreting B1a and B2 B cells in T2DM patients, their correlation with diabetes metabolic parameters and whether they play a role in diabetic foot infection (DFI) development. This study included 56 participants, recruited from Al-Zahraa hospital, Al-Azhar University, Egypt. Of these, 36 patients were diagnosed with T2DM, divided to two groups; (1) DM group (n=19) recently diagnosed, without foot complication; (2) DFI group (n=17); in addition to a Control group (n=20). The study assessed the frequency of circulating B1a (CD19+CD23-CD5+), and B2 (CD19+CD23+CD5-) cells by flow cytometry in diabetic patients. Comparison of the 3 studied groups revealed significant differences in frequency of studied total B cells (P=0.011), B1a (P < 0.001) and B2 subsets (P < 0.001). Comparison of B cell subsets between DFI, DM groups showed significant decrease in B1a in DFI group (P < 0.001). B1a cells % showed inverse correlation with HgA1c (r=-0.47, P < 0.001), LDL (r=-0.64, P < 0.001), and TG (r=-0.67, P < 0.001) but showed positive correlation with HDL (r=0.61, P < 0.001), while B2 cells showed opposite correlations. We concluded that imbalance of B cell subsets is seen in T2DM subjects. Beneficial role of B1a cells was spotted as they correlated inversely with glycemia and lipidemia in contrary to B2 cells. Decrease in B1a cells may predispose to DFI development.

RETRACTED: Extranodal natural killer/T-cell lymphoma masquerading a diabetic foot ulcer.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief due to an author reporting that they were listed without their permission.

Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization.

Inflammation is a critical phase in the healing of skin wounds. Excessive inflammation and inflammatory macrophages are known to cause impaired wound closure and outcome. This prompted us to test the role of IL-23 in IL-17 expression and in modulating wound inflammation and macrophage polarization. Full-thickness wounds (4 × 6 mm) were created on the dorsal surface of multiple genetically modified mouse models. Obese diabetic mouse wounds were treated with anti-IL-17A, anti-IL-23, or isotype-matched antibodies. We found IL-23- but not IL-12-deficient mice displayed significantly reduced IL-17 expression in wounds. This was rescued by delivery of recombinant IL-23. IL-23- and IL-17-deficient mice showed a significant increase in noninflammatory macrophages. Obese diabetic mice treated with anti-IL-17A and anti-IL-23p19 blocking antibodies had significantly improved wound reepithelialization. Similarly, IL-17-/- obese mice had accelerated wound closure, resulting in reduced iNOS expression and inflammatory macrophages while maintaining prohealing CD206 and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1)-expressing macrophages. This study highlights the importance of the IL-17 pathway in wound closure offering new possibilities of therapeutic intervention in chronic wounds.-Lee, J., Rodero, M. P., Patel, J., Moi, D., Mazzieri, R., Khosrotehrani, K. Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization.