Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans

Abstract

Proper healing of cutaneous wounds progresses through a series of overlapping phases. Non-healing wounds are defective in one or more of these processes and represent a major clinical problem. A critical issue in developing treatments for chronic wounds is the paucity of animal models to study the mechanisms underlying the defects in healing. Here we show that deletion of Tumor Necrosis Factor Superfamily Member 14 (TNFSF14/LIGHT) leads to impaired wounds in mice that have the characteristics of non-chronic and chronic ulcers. These wounds show: (1) Excessive production of cytokines, in particular three chemokines (KC/CXCL8, MCP-1/CCL2, IP-10/CXCL10), that may be key to the abnormal initiation and resolution of inflammation; (2) defective basement membranes, explaining blood vessel leakage and disruption of dermal/epidermal interactions; (3) granulation tissue that contains high levels of Coll III whereas Coll I is virtually absent and does not form fibrils. We also see major differences between non-chronic and chronic wounds, with the latter populated by bacterial films and producing eotaxin, a chemokine that attracts leukocytes that combat multicellular organisms (which biofilms can be considered to be). This new mouse model captures many defects observed in impaired and chronic human wounds, and provides a vehicle to address their underlying cell and molecular mechanisms.

Platelet Hyperactivity inTNFSF14/LIGHTKnockout Mouse Model of Impaired Healing

“…14 We have previously shown that TNFSF14/ LIGHT -/-mice display marked abnormalities in wound healing processes, including increased inflammation, oxidative and nitrosative stress, excessive coagulation and fibrin cuffs, vascular defects, and abnormal ECM deposition. 5,16 Furthermore, we also showed that the basement membrane of the blood vessels was not continuous, the microvessels had very few associated a-smooth muscle actin-expressing periendothelial cells, and contained significant intravascular coagulation, 16 resulting in immature/ defective vessels. Moreover, we have recently shown that in these mice with impaired healing, platelets have enhanced aggregation as well as shorter bleeding time.…”

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…126 Since macrophage apoptosis is important in the resolution of inflammation during wound healing, the authors propose that LIGHT-deficient wounds mimic chronic healing/nonhealing wounds in humans. 125 This work also implicates chemokines in chronic wound pathogenesis. Excess proinflammatory chemokine production (CXCL8, CCL2, and CXCL10) persisted from the early stages following injury, resulting in excess leukocyte infiltrates.…”

“…Excessive neutrophil infiltration is associated with unregulated MMP production and high levels of reactive oxygen species leading to increased inflammation, 127,128 whereas an increased duration of macrophage presence may lead to further protease-mediated damage of the healing tissue. 129 Crucially, premature and excessive CXCL10, resulted in early chemoattraction of T-lymphocytes, 125 which are usually associated with the remodeling phase of wound healing. 13 This suggests a disorganized healing process.…”

“…125 LIGHT mediates VEGF, a growth factor that induces macrophage apoptosis in vitro. 126 Since macrophage apoptosis is important in the resolution of inflammation during wound healing, the authors propose that LIGHT-deficient wounds mimic chronic healing/nonhealing wounds in humans.…”

Chemokines as Therapeutic Targets to Improve Healing Efficiency of Chronic Wounds

“…This resulted in reduced influx of neutrophils and macrophages, inhibition of angiogenesis, decrease in the number of myofibroblasts into the wounds, and eventually leading to delay in early skin wound healing. Patreaca et al 37 showed that deletion of TNF superfamily member 14 gene in mice leads to impaired wounds (mirrors human chronic wound); these mice showed excessive production of chemokines CXCL8, CXCL10, and CCL2 very early after wounding, which may have led to abnormal initiation and resolution of inflammation. In contrast, a diabetic rabbit ear wound model showed an increase in baseline gene expression of IL-6, IL-8, CXCR1, and CXCR2 postinjury and the expression was significantly less in diabetic wounds.…”