NLRP3 activation induced by neutrophil extracellular traps sustains inflammatory response in the diabetic wound

2019 ◽  
Vol 133 (4) ◽  
pp. 565-582 ◽  
Author(s):  
Dan Liu ◽  
Peilang Yang ◽  
Min Gao ◽  
Tianyi Yu ◽  
Yan Shi ◽  
...  
Keyword(s):  
Wound Healing ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Healing Process ◽  
Receptor Protein ◽  
Main Role ◽  
Diabetic Wound ◽  
Impaired Wound Healing ◽  
Extracellular Traps ◽  
Diabetic Wounds

Abstract Persistent inflammatory response in the diabetic wound impairs the healing process, resulting in significant morbidity and mortality. Mounting evidence indicate that the activation of Nod-like receptor protein (NLRP) 3 inflammasome in macrophages (MΦ) contributes to the sustained inflammatory response and impaired wound healing associated with diabetes. However, the main trigger of NLRP3 inflammasome in the wounds is not known. Neutrophils, as sentinels of the innate immune system and key stimulators of MΦ, are immune cells that play the main role in the early phase of healing. Neutrophils release extracellular traps (NETs) as defense against pathogens. On the other hand, NETs induce tissue damage. NETs have been detected in the diabetic wound and implicated in the impaired healing process, but the mechanism of NETs suspend wound healing and its role in fostering inflammatory dysregulation are elusive. Here, we report that NLRP3 and NETs production are elevated in human and rat diabetic wounds. NETs overproduced in the diabetic wounds triggered NLRP3 inflammasome activation and IL-1β release in MΦ. Furthermore, NETs up-regulated NLRP3 and pro-IL-1β levels via the TLR-4/TLR-9/NF-κB signaling pathway. They also elicited the generation of reactive oxygen species, which facilitated the association between NLRP3 and thioredoxin-interacting protein, and activated the NLRP3 inflammasome. In addition, NET digestion by DNase I alleviated the activation of NLRP3 inflammasome, regulated the immune cell infiltration, and accelerated wound healing in diabetic rat model. These findings illustrate a new mechanism by which NETs contribute to the activation of NLRP3 inflammasome and sustained inflammatory response in the diabetic wound.

651 NLRP3 Activation Induced by Neutrophil Extracellular Traps Sustains Inflammatory Response in the Diabetic Wound

2020 ◽  
Vol 41 (Supplement_1) ◽  
pp. S171-S172
Author(s):  
Dan Liu
Keyword(s):  
Wound Healing ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Healing Process ◽  
Dnase I ◽  
Cell Infiltration ◽  
Type I ◽  
Diabetic Wound ◽  
Extracellular Traps ◽  
Diabetic Wounds

Abstract Introduction Persistent inflammatory response in the diabetic wound impairs the healing process, resulting in significant morbidity and mortality. Mounting evidence indicates that the activation of NLRP3 inflammasome in macrophages (MF) contributes to the sustained inflammatory response and impaired wound healing associated with diabetes. However, the main trigger of NLRP3 inflammasome in the wounds is not known. Neutrophils, as sentinels of the innate immune system and key stimulators of MF, are immune cells that play the main role in the early phase of healing. Neutrophils release extracellular traps (NETs) as defense against pathogens. On the other hand, NETs induce tissue damage. NETs have been detected in the diabetic wound and implicated in the impaired healing process, but the mechanism of NETs suspend wound healing are elusive. Methods WB, immunofluorescence and immunocoprecipitation were used to detect the expression of NETs, NLRP3 inflammasome and IL-1b in diabetic foot ulcer wounds and the expression and activation of NLRP3 inflammsome after lowering the level of NETs. The role of NETs in activating macrophage inflammsome was verified and its mechanism was explored. Induced type I diabetic rats by STZ injection to detect the expression of NETs in the wound and observe the effects of exogenous DNase I on the expression of inflammasome and IL-1b in the wound, inflammatory cell infiltration and wound healing. Results NLRP3 and NETs are elevated in human and rat diabetic wounds. NETs overproduced in the diabetic wounds triggered NLRP3 inflammasome activation and IL-1b release. NETs up-regulated NLRP3 and pro-IL-1b levels via the TLR-4/TLR-9/NF-kB signalling pathway. NETs elicited ROS, which facilitated the association between NLRP3 and TXNIP, and activated the NLRP3 inflammasome. DNase I alleviated the activation of NLRP3 inflammasome, regulated the immune cell infiltration, and accelerated wound healing. Conclusions NETs contribute to the activation of NLRP3 inflammasome and sustained inflammatory response in the diabetic wound. NET digestion by DNase I alleviated the activation of NLRP3 inflammasome and accelerated wound healing. Applicability of Research to Practice

scholarly journals Molecular Changes in Diabetic Wound Healing following Administration of Vitamin D and Ginger Supplements: Biochemical and Molecular Experimental Study

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Hadeel A. Al-Rawaf ◽  
Sami A. Gabr ◽  
Ahmad H. Alghadir
Keyword(s):  
Vitamin D ◽  
Wound Healing ◽  
Wound Closure ◽  
Healing Process ◽  
Molecular Targets ◽  
Wound Healing Process ◽  
Diabetic Wound ◽  
Fibrin Deposition ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Background. Circulating micro-RNAs are differentially expressed in various tissues and could be considered as potential regulatory biomarkers for T2DM and related complications, such as chronic wounds. Aim. In the current study, we investigated whether ginger extract enriched with [6]-gingerol-fractions either alone or in combination with vitamin D accelerates diabetic wound healing and explores underlying molecular changes in the expression of miRNA and their predicted role in diabetic wound healing. Methods. Diabetic wounded mice were treated with [6]-gingerol-fractions (GF) (25 mg/kg of body weight) either alone or in combination with vitamin D (100 ng/kg per day) for two weeks. Circulating miRNA profile, fibrogenesis markers, hydroxyproline (HPX), fibronectin (FN), and collagen deposition, diabetic control variables, FBS, HbA1c, C-peptide, and insulin, and wound closure rate and histomorphometric analyses were, respectively, measured at days 3, 6, 9, and 15 by RT–PCR and immunoassay analysis. Results. Treatment of diabetic wounds with GF and vitamin D showed significant improvement in wound healing as measured by higher expression levels of HPX, FN, collagen, accelerated wound closure, complete epithelialization, and scar formation in short periods (11-13 days, (P<0.01). On a molecular level, three circulating miRNAs, miR-155, miR-146a, and miR-15a, were identified in diabetic and nondiabetic skin wounds by PCR analysis. Lower expression in miR-155 levels and higher expression of miR-146a and miR-15a levels were observed in diabetic skin wounds following treatment with gingerols fractions and vitamin D for 15 days. The data showed that miRNAs, miR-146a, miR-155, and miR-15a, correlated positively with the expression levels of HPX, FN, and collagen and negatively with FBS, HbA1c, C-peptide, and insulin in diabetic wounds following treatment with GF and /or vitamin D, respectively. Conclusion. Treatment with gingerols fractions (GF) and vitamin D for two weeks significantly improves delayed diabetic wound healing. The data showed that vitamin D and gingerol activate vascularization, fibrin deposition (HPX, FN, and collagen), and myofibroblasts in such manner to synthesize new tissues and help in the scar formation. Accordingly, three miRNAs, miR-155, miR-146a, and miR-15, as molecular targets, were identified and significantly evaluated in wound healing process. It showed significant association with fibrin deposition, vascularization, and reepithelialization process following treatment with GF and vitamin D. It proposed having anti-inflammatory action and promoting new tissue formation via vascularization process during the wound healing. Therefore, it is very interesting to consider miRNAs as molecular targets for evaluating the efficiency of nondrug therapy in the regulation of wound healing process.

scholarly journals The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice

2018 ◽  
Vol 19 (11) ◽  
pp. 3289 ◽  
Author(s):  
James Lee ◽  
Avril Robertson ◽  
Matthew Cooper ◽  
Kiarash Khosrotehrani
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Nlrp3 Inflammasome ◽  
Chronic Wounds ◽  
Inflammatory Diseases ◽  
Healing Process ◽  
Obese Mice ◽  
Impaired Wound Healing ◽  
Macrophage Polarisation ◽  
Inflammatory Conditions

The incidence of chronic wounds is escalating, and the associated healing process is especially problematic in an aging population with increased morbidity. Targeting increased inflammation in chronic wounds is a promising but challenging therapeutic strategy. Indeed, inflammation and especially macrophages are required for wound healing. As the NLRP3 inflammasome has been implicated with various other inflammatory diseases, in this study, we used MCC950—a selective NLRP3 small molecule inhibitor—on murine models of both acute and chronic wounds. This molecule, while tested for other inflammatory conditions, has never been investigated to reduce topical inflammation driving chronic wounds. We found that there were no significant differences when the treatment was applied either topically or orally in wild-type C57Bl/6 mice and that it even impaired wound healing in obese mice. The treatment was also unable to improve re-epithelialisation or angiogenesis, which are both required for the closure of wounds. We are inclined to believe that MCC950 may inhibit the closure of chronic wounds and that it does not alter wound-associated macrophage polarisation.

scholarly journals Diabetic Wound Care: A Concise Review of Diabetic Wound and Skincare Ingredients

2020 ◽  
Vol 8 (2) ◽  
Author(s):  
Mohammad Afsahi ◽  
Hamid Reza Ahmadi Ashtiani ◽  
Amir Hosein Askari Pour ◽  
Ebrahim Hazrati
Keyword(s):  
Wound Healing ◽  
Wound Care ◽  
Healing Process ◽  
Topical Administration ◽  
The Body ◽  
Wound Healing Process ◽  
Diabetic Wound ◽  
Normal Wound Healing ◽  
Healing Wounds ◽  
Diabetic Wounds

: Chronic wound healing remains a complicated issue in the world's scientific health society. Alterations in the human body conditions such as biochemical, immunological, and physiological states may lead to non-healing wounds, making the treatment an insurmountably long and expensive procedure. Diabetes mellitus disposes the body to many complicated conditions while preventing diabetic wounds away from the normal wound-healing process. As topical administration is a favorable route of treating wounds, here, in this article, different topical materials and their roles are briefly reviewed.

scholarly journals Topical insulin application accelerates diabetic wound healing by promoting anti-inflammatory macrophage polarization

2020 ◽  
Vol 133 (19) ◽  
pp. jcs235838
Author(s):  
Peilang Yang ◽  
Xiqiao Wang ◽  
Di Wang ◽  
Yan Shi ◽  
Meng Zhang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Macrophage Polarization ◽  
Healing Process ◽  
Polarization State ◽  
Wound Healing Process ◽  
Diabetic Wound ◽  
Insulin Degrading Enzyme ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

ABSTRACTBesides regulating glucose levels, insulin has been reported to participate actively in many other functions, including modulating inflammatory reactions. In this study we investigated how topical insulin application would affect the diabetic wound healing process. We found that the excessive expression of insulin-degrading enzyme led to insufficient insulin levels in diabetic skin during wound healing, which ultimately reduced the recovery rate of diabetic wounds. We confirmed that topical insulin application could reverse the impaired inflammation reaction in the diabetic wound environment and promote healing of diabetic wounds. Our study revealed that insulin promoted apoptosis of neutrophils and subsequently triggered polarization of macrophages. Both in vivo and in vitro studies verified that insulin re-established phagocytosis function and promoted the process of phagocytosis-induced apoptosis in neutrophils. Furthermore, we found that insulin treatment also promoted efferocytosis of the apoptosed neutrophils by macrophages, and thus induced macrophages to change their polarization state from M1 to M2. In conclusion, our studies proved that the exogenous application of insulin could improve diabetic wound healing via the restoration of the inflammatory response.

scholarly journals The Influence of Flightless I on Toll-Like-Receptor-Mediated Inflammation in a Murine Model of Diabetic Wound Healing

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Nadira Ruzehaji ◽  
Stuart J. Mills ◽  
Elizabeth Melville ◽  
Ruth Arkell ◽  
Robert Fitridge ◽  
...  
Keyword(s):  
Wound Healing ◽  
Inflammatory Response ◽  
Murine Model ◽  
Wound Repair ◽  
Adaptor Protein ◽  
Diabetic Mouse ◽  
Impaired Wound Healing ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Impaired wound healing and ulceration represent a serious complication of both type 1 and type 2 diabetes. Cytoskeletal protein Flightless I (Flii) is an important inhibitor of wound repair, and reduced Flii gene expression in fibroblasts increased migration, proliferation, and adhesion. As such it has the ability to influence all phases of wound healing including inflammation, remodelling and angiogenesis. Flii has the potential to modulate inflammation through its interaction with MyD88 which it an adaptor protein for TLR4. To assess the effect of Flii on the inflammatory response of diabetic wounds, we used a murine model of streptozocin-induced diabetes and Flii genetic mice. Increased levels of Flii were detected in Flii transgenic murine wounds resulting in impaired healing which was exacerbated when diabetes was induced. When Flii levels were reduced in diabetic wounds of Flii-deficient mice, healing was improved and decreased levels of TLR4 were observed. In contrast, increasing the level of Flii in diabetic mouse wounds led to increased TLR4 and NF-κB production. Treatment of murine diabetic wounds with neutralising antibodies to Flii led to an improvement in healing with decreased expression of TLR4. Decreasing the level of Flii in diabetic wounds may therefore reduce the inflammatory response and improve healing.

scholarly journals Sustained Oxygenation Accelerates Diabetic Wound Healing by Simultaneously Promoting Epithelialization and Angiogenesis, and Decreasing Tissue Inflammation

2021 ◽  
Author(s):  
Ya Guan ◽  
Hong Niu ◽  
Zhongting Liu ◽  
Yu Dang ◽  
Jie Shen ◽  
...  
Keyword(s):  
Wound Healing ◽  
Healing Process ◽  
Dermal Fibroblasts ◽  
Diabetic Patients ◽  
Diabetic Wound ◽  
Oxygen Release ◽  
Ros Scavenging ◽  
M1 Macrophage ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Non-healing diabetic wound is one of the most common complications for diabetic patients. Chronic hypoxia is among the prominent factors that delay the wound healing process. Therefore, sustained oxygenation to alleviate hypoxia is hypothesized to promote diabetic wound healing. Yet it cannot be achieved by current clinical approaches including hyperbaric oxygen therapy. Herein, we developed a sustained oxygenation system consisting of oxygen-release microspheres and a reactive oxygen species (ROS)-scavenging hydrogel. The hydrogel was used to capture the ROS that is elevated in the diabetic wounds, and that may be generated due to oxygen release. The sustainedly released oxygen augmented survival and migration of keratinocytes and dermal fibroblasts; promoted angiogenic growth factor expression, and angiogenesis in the diabetic wounds; and decreased M1 macrophage density. These effects led to a significant increase of wound closure rate. These findings reveal that sustained oxygenation alone without using drugs is capable of healing diabetic wounds.

Diabetic wound healing approaches: an update

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Raghuvir Keni ◽  
Farmiza Begum ◽  
Karthik Gourishetti ◽  
Gollapalle Lakshminarayanashastry Viswanatha ◽  
Pawan Ganesh Nayak ◽  
...  
Keyword(s):  
Wound Healing ◽  
Diabetic Foot ◽  
Healing Process ◽  
Clinical Importance ◽  
Diagnostic Tools ◽  
Wound Infections ◽  
Diabetic Wound ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Abstract Diabetic wounds are of profound clinical importance. Despite immense efforts directed towards its management, it results in the development of amputations, following a diagnosis of diabetic foot. With a better understanding of the complexities of the microbalance involved in the healing process, researchers have developed advanced methods for the management of wounds as well as diagnostic tools (especially, for wound infections) to be delivered to clinics sooner. In this review, we address the newer developments that hope to drive the transition from bench to bedside in the coming decade.

scholarly journals Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
YiFeng Yuan ◽  
Sushant K. Das ◽  
MaoQuan Li
Keyword(s):  
Vitamin D ◽  
Wound Healing ◽  
Inflammatory Responses ◽  
Vitamin D Supplementation ◽  
Diabetic Wound ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Diabetic wounds are characterized by delayed wound healing due to persistent inflammation and excessive production of reactive oxygen species. Vitamin D, which is well acknowledged to enhance intestinal calcium absorption and increase in plasma calcium level, has recently been shown to display beneficial effects in various vascular diseases by promoting angiogenesis and inhibiting inflammatory responses. However, the role of Vitamin D in diabetic wound healing is still unclear. In the present study, we investigated the role of Vitamin D in cutaneous wound healing in streptozotocin (STZ)-induced diabetic mice. Four weeks after injection of STZ, a full thickness excisional wound was created with a 6-mm diameter sterile biopsy punch on the dorsum of the mice. Vitamin D was given consecutively for 14 days by intraperitoneal injection. Vitamin D supplementation significantly accelerated wound healing in diabetic mice and improved the healing quality as assessed by measuring the wound closure rate and histomorphometric analyses. By monitoring the level of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL) 6 (IL-6), IL-1β) in the wounds, reduced inflammatory response was found in VD treatment group. Furthermore, nuclear factor κB (NF-κB) pathway was found to be involved in the process of diabetic wound healing by assessing the relative proteins in diabetic wounds. Vitamin D supplementation obviously suppressed NF-κB pathway activation. These results demonstrated that Vitamin D improves impaired wound healing in STZ-induced diabetic mice through suppressing NF-κB-mediated inflammatory gene expression.

scholarly journals Recovery of Altered Diabetic Myofibroblast Heterogeneity and Gene Expression Associated with CD301b+ Macrophages

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1752
Author(s):  
MaryEllen R. Haas ◽  
Darlene V. Nguyen ◽  
Brett A. Shook
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Healing Process ◽  
Mouse Skin ◽  
Tissue Analysis ◽  
Diabetic Wound ◽  
Phenotypic Switch ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds ◽  
And Control

Diabetic wound healing is associated with impaired function and reduced numbers of myofibroblasts, a heterogeneous cell population with varying capacities to promote repair. To determine how diabetes alters myofibroblast composition, we performed flow cytometry and spatial tissue analysis of myofibroblast subsets throughout the healing process in diabetic (db/db) and control (db/+) mouse skin. We observed reduced numbers of profibrotic SCA1+; CD34+; CD26+ myofibroblasts in diabetic wounds five days after injury, with decreased expression of fibrosis-associated genes compared to myofibroblasts from db/+ mouse wounds. While the abundance of myofibroblasts remained reduced in db/db mouse wounds compared to controls, the altered myofibroblast heterogeneity and gene expression in diabetic mice was improved seven days after injury. The natural correction of myofibroblast composition and gene expression in db/db wound beds temporally corresponds with a macrophage phenotypic switch. Correlation analysis from individual wound beds revealed that wound healing in control mice is associated with CD206+ macrophages, while the rescued myofibroblast phenotypes in diabetic wounds are correlated with increased CD301b+ macrophage numbers. These data demonstrate how diabetes impacts specific subsets of myofibroblasts and indicate that signaling capable of rescuing impaired diabetic wound healing could be different from signals that regulate wound healing under nonpathological conditions.

Sign in / Sign up

Export Citation Format

Share Document