S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

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

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.

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

BACKGROUND: Burns 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. METHODS: In 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). RESULTS: In 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. CONCLUSION: Montelukast delays wound healing mainly by reducing the proliferation of local cells after burn injury. CLINICAL RELEVANCE STATEMENT: Although additional and clinical studies are necessary, our study suggests that burn patients who are on montelukast may exhibit delayed healing, necessitating extra observation.

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.

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.

Microbiome-skin-brain axis: A novel paradigm for cutaneous wounds.

Chronic wounds cause a significant burden on society financially, medically, and psychologically. Unfortunately, patients with nonhealing wounds often suffer from comorbidities that further compound their disability. Given the high rate of depressive symptoms experienced by patients with chronic wounds, further studies are needed to investigate the potentially linked pathophysiological changes in wounds and depression in order to improve patient care. The English literature on wound healing, inflammatory and microbial changes in chronic wounds and depression, and antiinflammatory and probiotic therapy was reviewed on PubMed. Chronic wound conditions and depression were demonstrated to share common pathologic features of dysregulated inflammation and altered microbiome, indicating a possible relationship. Furthermore, alternative treatment strategies such as immune-targeted and probiotic therapy showed promising potential by addressing both pathophysiological pathways. However, many existing studies are limited to a small study population, a cross-sectional design that does not establish temporality, or a wide range of confounding variables in the context of a highly complex and multifactorial disease process. Therefore, additional preclinical studies in suitable wound models, as well as larger clinical cohort studies and trials are necessary to elucidate the relationship between wound microbiome, healing, and depression, and ultimately guide the most effective therapeutic and management plan for chronic wound patients.

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.