Role of NK Cells in Skin Wound Healing of Mice.

NK cells are best known for their killing of virus-infected cells and tumor cells via release of cytotoxic factors. However, NK cells can also produce growth factors and cytokines, and thus have the potential to influence physiological processes such as wound healing. In this study, we test the hypothesis that NK cells play a physiological role in skin wound healing of C57BL/6J mice. Immunohistochemical and flow cytometry assays showed that NK cells accumulate in excisional skin wounds, peaking on day 5 postinjury. We also found that NK cells proliferate locally in wounds, and blocking IL-15 activity locally reduces NK cell proliferation and accumulation in wounds. Wound NK cells exhibit primarily a mature CD11b+CD27- and NKG2A+NKG2D- phenotype and express LY49I and proinflammatory cytokines such as IFN-γ, Tnf-a, and Il-1ß. Systemic depletion of NK cells resulted in enhanced re-epithelization and collagen deposition, suggesting a negative role for these cells in skin wound healing. Depletion of NK cells did not influence accumulation of neutrophils or monocytes/macrophages in wounds but did reduce expression of IFN-γ, Tnf-a, and Il-1ß, indicating that NK cells contribute to proinflammatory cytokine expression in wounds. In short, NK cells may impede physiological wound healing via production of proinflammatory cytokines.

Liver insulin-like growth factor-1 mediates effects of low-intensity vibration on wound healing in diabetic mice.

Chronic wounds in diabetic patients are associated with significant morbidity and mortality; however, few therapies are available to improve healing of diabetic wounds. Our group previously reported that low-intensity vibration (LIV) could improve angiogenesis and wound healing in diabetic mice. The purpose of this study was to begin to elucidate the mechanisms underlying LIV-enhanced healing. We first demonstrate that LIV-enhanced wound healing in db/db mice is associated with increased IGF1 protein levels in liver, blood, and wounds. The increase in insulin-like growth factor (IGF) 1 protein in wounds is associated with increased Igf1 mRNA expression both in liver and wounds, but the increase in protein levels preceded the increase in mRNA expression in wounds. Since our previous study demonstrated that liver was a primary source of IGF1 in skin wounds, we used inducible ablation of IGF1 in the liver of high-fat diet (HFD)-fed mice to determine whether liver IGF1 mediated the effects of LIV on wound healing. We demonstrate that knockdown of IGF1 in liver blunts LIV-induced improvements in wound healing in HFD-fed mice, particularly increased angiogenesis and granulation tissue formation, and inhibits the resolution of inflammation. This and our previous studies indicate that LIV may promote skin wound healing at least in part via crosstalk between the liver and wound. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Targeting the NOD-Like Receptor Pyrin Domain Containing 3 Inflammasome to Improve Healing of Diabetic Wounds.

Significance: Chronic skin wounds are a significant health problem around the world, often leading to amputation and even death. Although persistent inflammation is a hallmark of these poorly healing wounds, few available therapies have been designed to target inflammation. In this review, we summarize available evidence of the role of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in impaired wound healing and describe strategies to inhibit the inflammasome to improve wound healing. Recent Advances: The NLRP3 inflammasome plays an important physiological role in skin wound healing, during which transient inflammasome activity contributes to both epidermal and dermal healing. In contrast, sustained activity of the NLRP3 inflammasome leads to impaired epidermal and dermal healing associated with diabetes. Of importance, preclinical studies have demonstrated that inhibiting the NLRP3 inflammasome-induced resolution of inflammation, increased granulation tissue formation and collagen deposition, and accelerated reepithelialization and wound closure. Critical Issues: NLRP3 inflammasome inhibitors have appealing potential for translation into therapies for chronic wounds. Although preclinical studies have shown promising results, there is a need for human/clinical studies to evaluate dosing formulations, potential therapeutic effects, dose-response relationships, and possible side effects. Future Directions: Among strategies to inhibit the NLRP3 inflammasome, glyburide, metformin, peroxisome proliferator-activated receptor agonists, and the dipeptidyl peptidase 4 inhibitor saxagliptin appear to be closest to clinical translation, as these drugs are already Food and Drug Administration approved for other indications. Future clinical studies are needed to develop topical formulations of these drugs, and to assess the safety and efficacy of these inhibitors, to improve healing of chronic wounds.

Ischemia-reperfusion damage is attenuated by GQ-11, a peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, after aorta clamping in rats.

INTRODUCTION: Ischemia-Reperfusion (I/R) damage is one of the major challenges in cardiothoracic surgeries and in a pathological manner, is identified by exacerbated damage signals resulted from blood supply restriction and subsequent flow restoration and re­oxygenation. I/R damage includes cellular dysfunction and death, impairing tissue and organ function. Inflammation and oxidative stress are known to underlie either ischemia or reperfusion, leaded by HIF, TNF-α, NF-κB, IL-6 and ROS formation. However, the available approaches to prevent I/R damage has been unsuccessful so far. As agonists of peroxisome-proliferation activation receptor (PPAR) are described as transcription factors related to anti-inflammatory factors, we proposed to observe the effects of novel dual agonist, GQ-11, in I/R-related damage. METHODS: Male, Wistar rats, 60 days age and 305 g body weight average were treated with vehicle, pioglitazone or GQ-11 (20 mg/kg) for 7 consecutive days and were submitted to aorta clamping for 30 min followed by 3 h of reperfusion. 18F-fluorodeoxyglucose (18F-FDG), an analog of glucose associated with inflammation when accumulated, was observed in liver and bowel by positron emission tomography (PET). RESULTS: GQ-11 decreased 18F-FDG uptake in liver and bowel when compared to vehicle and pioglitazone. The treatment also modulated inflammatory markers IL-10, TGF-ß, IL-6, IL1-ß, TNFα, and CCL-2, besides antioxidant enzymes such as catalase, GPx and SOD. CONCLUSION: Inflammation and oxidative stress showed to be important processes to be regulated in I/R in order to prevent exacerbated responses that leads to cell/tissue dysfunction and death. PPAR agonists - including GQ-11 - might be promising agents in a strategy to avoid tissue dysfunction and death after cardiothoracic surgeries.

Liver is a primary source of insulin-like growth factor-1 in skin wound healing.

Insulin-like growth factor (IGF)-1 plays important role in tissue repair through its ability to stimulate wound cell activity. While IGF-1 is expressed locally by wound cells, liver-derived IGF-1 is also present at high levels in the circulation, and the contributions of local vs circulating IGF-1 to wound levels remain undefined. The hypothesis of this study was that liver is a primary source of IGF-1 during skin wound healing. To test this hypothesis, we utilized a model that allows inducible ablation of IGF-1 specifically in liver of adult mice. We demonstrate that ablation of liver IGF-1 leads to >85% loss of circulating IGF-1 and ~60% decrease in wound IGF-1 during the proliferative phase of healing in both male and female mice. This reduction of liver-derived IGF-1 did not alter local mRNA expression of Igf1 in wounds. Knockdown of liver IGF-1 significantly delayed wound re-epithelialization and reduced granulation tissue formation and collagen deposition. Knockdown of liver IGF-1 also significantly reduced angiogenesis and resulted in persistent macrophage accumulation. In summary, liver is a primary source of IGF-1 in skin wounds and contributes to many aspects of both epithelial and dermal healing.