Basaloid skin tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma (BFH), are associated with aberrant Hedgehog (Hh) signaling1 and, in the case of BCC, an expanding set of genetic variants including keratin 5 (K5)2, an intermediate filament-forming protein. We show that genetic ablation of keratin 17 (K17) protein, which is induced in basaloid skin tumors3,4 and co-polymerizes with K5 in vivo5, delays BFH tumor initiation and growth in mice with constitutive Hh signaling in epidermis6,7. The delay is preceded by reduced inflammation and a polarization of inflammatory cytokines from a Th1/Th17- to a Th2-dominated profile. Absence of K17 also attenuates hyperplasia and inflammation in a model of acute dermatitis. Re-expression of K17 in Gli2tg K17−/− keratinocytes induces select Th1 chemokines with established roles in BCC. Our findings establish a novel immunomodulatory role for K17 in Hh-driven basaloid skin tumors that could impact additional tumor settings, psoriasis, and wound repair.

Epidermolysis bullosa (EB) simplex is a rare genetic condition typified by superficial bullous lesions that result from frictional trauma to the skin. Most cases are due to dominantly acting mutations in either keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins tasked with forming a pancytoplasmic network of 10-nm filaments in basal keratinocytes of the epidermis and in other stratified epithelia. Defects in K5/K14 filament network architecture cause basal keratinocytes to become fragile and account for their trauma-induced rupture. Here we review how laboratory investigations centered on keratin biology have deepened our understanding of the etiology and pathophysiology of EB simplex and revealed novel avenues for its therapy.Introduction to epidermolysis bullosa simplex Epidermolysis bullosa (EB) is a grouping of rare genetic conditions in which bullous lesions (fluid-filled cavities, or blisters, larger than 0.5 cm) affecting primarily the skin arise after exposure to mechanical trauma (1). Three major forms of EB have been defined using clinical and histological criteria. The dystrophic, junctional, and simplex forms of EB are characterized by loss of tissue integrity in the upper dermis, at the dermo-epidermal interface, and within the epidermis, respectively (Figure 1) (2, 3). With rare exceptions, EB simplex is inherited in an autosomal dominant fashion. Although EB simplex is the most frequently occurring form of EB (approximately 1 case per 25,000 live births), it also is the least severe (2, 4-6). In this Review, we summarize current knowledge of the etiology and pathophysiology of EB simplex, discuss what this condition tells us about the properties and roles of keratin, and outline progress toward therapeutic intervention.In EB simplex, trauma-induced loss of tissue integrity consistently occurs within the basal layer of epidermal keratinocytes (Figures 1 and 2). The inherited defect renders basal keratinocytes fragile, causing them to rupture when the epidermis (and, in some cases, other stratified epithelia) is subjected to mechanical stress (Figures 1 and 2). Associated skin pigmentation anomalies can occur (see below), but terminal epithelial cell differentiation and epidermal barrier function appear normal.Several clinical variants of EB simplex have been described. The most frequent and widely known variants - EB simplex-generalized (EBS-generalized; in which the distribution of blistering is "generalized" over the body), EB simplex-localized (in which the distribution of blistering is "localized," e.g., primarily restricted to hands and feet), and EB simplex Dowling-Meara (EBS-DM; in which blisters are also generalized but show a distinct "herpetiform" or clustered pattern) - differ primarily according to the distribution, frequency, and severity of skin blistering over the body (Table 1). These variants also show key ultrastructural differences ( Figure 3) and vary in the involvement of other epithelia and their prognosis (Table 1). Other forms of EB simplex are les...

Hidradenitis suppurativa (HS), also known as acne inversa, is an incapacitating skin disorder of unknown etiology manifested as abscess-like nodules and boils resulting in fistulas and tissue scarring as it progresses. Given that neutrophils are the predominant leukocyte infiltrate in HS lesions, the role of neutrophil extracellular traps (NETs) in the induction of local and systemic immune dysregulation in this disease was examined. Immunofluorescence microscopy was performed in HS lesions and detected the prominent presence of NETs. NET complexes correlated with disease severity, as measured by Hurley staging. Neutrophils from the peripheral blood of patients with HS peripheral also displayed enhanced spontaneous NET formation when compared to healthy control neutrophils. Sera from patients recognized antigens present in NETs and harbored increased antibodies reactive to citrullinated peptides. B cell dysregulation, as evidenced by elevated plasma cells and IgG, was observed in the circulation and skin from patients with HS. Peptidylarginine deiminases (PADs) 1 to 4, enzymes involved in citrullination, were differentially expressed in HS skin, when compared to controls, in association with enhanced tissue citrullination. NETs in HS skin coexisted with plasmacytoid dendritic cells, in association with a type I interferon (IFN) gene signature. Enhanced NET formation and immune responses to neutrophil and NET-related antigens may promote immune dysregulation and contribute to inflammation. This, along with evidence of up-regulation of the type I IFN pathway in HS skin, suggests that the innate immune system may play important pathogenic roles in this disease.

The isothiocyanate sulforaphane was isolated from broccoli extracts in a bioactivity-guided fractionation as the principal and very potent inducer of cytoprotective phase 2 enzymes and subsequently shown to inhibit tumor development in animal models that involve various carcinogens and target organs. Because broccoli and broccoli sprouts are widely consumed, extracts obtained from them are viewed as convenient vehicles for sulforaphane delivery to humans. In relation to our current interest in devising strategies for protection against UV light-induced skin cancer, it was necessary to examine the safety and efficacy of topical application of sulforaphane-containing broccoli sprout extracts as single and multiple doses in both mice and humans. Topical application of an extract delivering 100 nmol sulforaphane/ cm 2 increased the protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase A1, and heme oxygenase 1, three representative phase 2 enzymes, in mouse skin epidermis. Quantitative assessment of the activity of NQO1 24 h after dosing showed increases of 1.5-and 2.7-fold after application of single and multiple (thrice, every 24 h) doses, respectively. A dose-escalation safety study in healthy human subjects revealed no adverse reactions when doses as high as 340 nmol of sulforaphane in the form of broccoli sprout extracts were applied topically to the center of a 1-cmdiameter circle drawn on the volar forearm. A subsequent efficacy study showed that despite the interindividual differences in basal levels, the enzyme activity of NQO1 in homogenates of 3-mm full thickness skin punch biopsies increased in a dose-dependent manner, with maximum increases of 1.5-and 4.5-fold after application of 150 nmol doses, once or three times (at 24 h-intervals), respectively, thus providing direct evidence for induction of the phase 2 response in humans. (Cancer Epidemiol Biomarkers Prev 2007;16(4):847-51)