TRPV1: Role in Skin and Skin Diseases and Potential Target for Improving Wound Healing

Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient receptor potential cation channel, subfamily V member 1 (TRPV1) in wound healing, with the intent of targeting it in treatment of non-healing wounds. TRPV1 structure and function as well as the outcomes of TRPV1-targeted therapies utilized in several diseases and tissues are summarized. In skin, keratinocytes, sebocytes, nociceptors, and several immune cells express TRPV1, making it an attractive focus area for treating wounds. Many intrinsic and extrinsic factors confound the function and targeting of TRPV1 and may lead to adverse or off-target effects. Therefore, a better understanding of what is known about the role of TRPV1 in skin and wound healing will inform future therapies to treat impaired and chronic wounds to improve healing

TRPV1: Role in Skin and Skin Diseases and Potential Target for Improving Wound Healing.

Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient receptor potential cation channel, subfamily V member 1 (TRPV1) in wound healing, with the intent of targeting it in treatment of non-healing wounds. TRPV1 structure and function as well as the outcomes of TRPV1-targeted therapies utilized in several diseases and tissues are summarized. In skin, keratinocytes, sebocytes, nociceptors, and several immune cells express TRPV1, making it an attractive focus area for treating wounds. Many intrinsic and extrinsic factors confound the function and targeting of TRPV1 and may lead to adverse or off-target effects. Therefore, a better understanding of what is known about the role of TRPV1 in skin and wound healing will inform future therapies to treat impaired and chronic wounds to improve healing

Interleukin-17: Potential Target for Chronic Wounds.

Chronic wounds exhibit persistent inflammation with markedly delayed healing. The significant burden of chronic wounds, which are often resistant to standard therapy, prompts further research on novel therapies. Since the interleukin-17 family has been implicated as a group of proinflammatory cytokines in immune-mediated diseases in the gut and connective tissue, as well as inflammatory skin conditions, we consider here if it may contribute to the pathogenesis of chronic wounds. In this review, we discuss the interleukin-17 family's signaling pathways and role in tissue repair. A PubMed review of the English literature on interleukin-17, wound healing, chronic wounds, and inflammatory skin conditions was conducted. Interleukin-17 family signaling is reviewed in the context of tissue repair, and preclinical and clinical studies examining its role in the skin and other organ systems are critically reviewed. The published work supports a pathologic role for interleukin-17 family members in chronic wounds, though this needs to be more conclusively proven. Clinical studies using monoclonal interleukin-17 antibodies to improve healing of chronic skin wounds have not yet been performed, and only a few studies have examined interleukin-17 family expression in chronic skin wounds. Furthermore, different interleukin-17 family members could be playing selective roles in the repair process. These studies suggest a therapeutic role for targeting interleukin-17A to promote wound healing; therefore, interleukin-17A may be a target worthy of pursuing in the near future

Montelukast, an Antagonist of Cysteinyl Leukotriene Signaling, Impairs Burn Wound Healing

BackgroundBurns are severe injuries often associated with impaired wound healing. Impaired healing is caused by multiple factors, including dysregulated inflammatory responses at the wound site. Interestingly, montelukast, an antagonist for cysteinyl leukotrienes and U.S. Food and Drug Administration approved for treatment of asthma and allergy, was previously shown to enhance healing in excision wounds and to modulate local inflammation.MethodsIn this study, the authors examined the effect of montelukast on wound healing in a mouse model of scald burn injury. Burn wound tissues isolated from montelukast- and vehicle-treated mice at various times after burn injury were analyzed for wound areas ( n = 34 to 36), reepithelialization ( n = 14), inflammation ( n = 8 to 9), and immune cell infiltration ( n = 3 to 6) and proliferation ( n = 7 to 8).ResultsIn contrast to previously described beneficial effects in excision wounds, this study shows that montelukast delays burn wound healing by impairing the proliferation of keratinocytes and endothelial cells. This occurs largely independently of inflammatory responses at the wound site, suggesting that montelukast impairs specifically the proliferative phase of wound healing in burns. Wound healing rates in mice in which leukotrienes are not produced were not affected by montelukast.ConclusionMontelukast delays wound healing mainly by reducing the proliferation of local cells after burn injury.Clinical relevance statementAlthough additional and clinical studies are necessary, our study suggests that burn patients who are on montelukast may exhibit delayed healing, necessitating extra observation

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice.

Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)-based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia-preconditioned, allogeneic human MSCs combined with the beta-adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 μM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 105  cells/cm2 on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7-day treatment, accumulative steady-state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro-inflammatory cytokines IL-1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti-inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5-fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds

Staphylococcus epidermidis activates keratinocyte cytokine expression and promotes skin inflammation through the production of phenol-soluble modulins

Summary: Staphylococcus epidermidis is a common microbe on human skin and has beneficial functions in the skin microbiome. However, under conditions of allergic inflammation, the abundance of S. epidermidis increases, establishing potential danger to the epidermis. To understand how this commensal may injure the host, we investigate phenol-soluble modulin (PSM) peptides produced by S. epidermidis that are similar to peptides produced by Staphylococcus aureus. Synthetic S. epidermidis PSMs induce expression of host defense genes and are cytotoxic to human keratinocytes. Deletion mutants of S. epidermidis lacking these gene products support these observations and further show that PSMs require the action of the EcpA bacterial protease to induce inflammation when applied on mouse skin with an intact stratum corneum. The expression of PSMδ from S. epidermidis is also found to correlate with disease severity in patients with atopic dermatitis. These observations show how S. epidermidis PSMs can promote skin inflammation