Keratinocyte Hyperplasia Research Articles

P69 Modelling epidermal melanocyte behaviour during plaque psoriasis progression and resolution

Abstract Melanocytes in human epidermis reside in the basal layer in a ratio of 1 melanocyte to ∼10 keratinocytes. In healthy epidermis, melanocytes neither divide nor undergo apoptosis. In psoriasis, the 1:10 ratio is maintained despite significant keratinocyte hyperplasia, suggesting an increase in melanocyte numbers. We investigated whether melanocyte numbers change in active psoriasis plaques and after plaque resolution upon treatment with biologics, and via the impact of psoriasis-related cytokines on melanogenesis in primary normal melanocytes in vitro. Immunohistochemistry (IHC) with MITF (melanocyte marker) and Ki67 (proliferation marker) on lesional and non-lesional samples (n = 11) at baseline and after 12 weeks of treatment assessed melanocyte proliferation. Melanocyte number/mm of basal layer and melanocyte/keratinocyte ratio were estimated by analysis on ImageJ. The TUNEL-assay and IHC staining with pro-apoptotic marker, Cleaved Caspase 3, and anti-apoptotic marker, BCL-2 were performed on lesional and non-lesional samples (n = 5) at baseline and after 4 and 12 weeks of treatment to determine if melanocytes undergo apoptosis upon treatment with biologics. Primary normal human melanocytes were treated with proinflammatory cytokines (IL-17, TNF-α, IL-22, and IL-23) to assess their influence on melanogenesis via immunocytochemistry (ICC) and Western blot (WB) analysis. Proliferating melanocytes were detected in non-lesional and lesional samples and in resolving plaques after treatment but not in healthy control epidermis. Melanocyte number/mm of the basal layer was significantly higher in non-lesional compared with both lesional sections and healthy controls (P < 0.0001), suggesting melanocyte expansion occurs prior to psoriasis plaque establishment. Twelve weeks after treatment, melanocyte numbers in lesional and non-lesional samples were still significantly higher than controls (P < 0.05) despite the reduction in keratinocyte numbers. The TUNEL-assay and Cleaved Caspase 3 staining did not detect evidence of melanocyte apoptosis. ICC and WB analysis of treated primary melanocytes revealed that TNF-α decreases the activity of the rate-limiting melanogenesis enzyme tyrosinase and down-regulates TRP1 both when this cytokine was used alone and in combination with the other cytokines. This study shows early melanocyte dysregulation supporting a role for melanocytes in psoriasis pathogenesis perhaps via an ADAMSTL5-initiated inflammation. The higher melanocyte numbers are retained even after treatment, and we were unable to detect melanocyte deletion/apoptosis despite a reduction in keratinocyte number. We show the direct inhibitory impact of psoriasis-associated cytokines on melanogenesis. This raises intriguing questions as to the nature of melanocyte proliferation in this benign inflammatory skin disease and suggests that such ectopic melanocytic proliferation in the epidermis may not be a harbinger of malignancy risk.

Eugenol-Loaded Lipid Nanoparticles-Derived Hydrogels Ameliorate Psoriasis-like Skin Lesions by Lowering Oxidative Stress and Modulating Inflammation.

Psoriasis is a chronic T-cell-mediated autoimmune skin disorder characterized by excessive epidermal thickening, overproliferation of keratinocyte, disruption of epidermal cell differentiation, and increased blood vessel growth in the dermal layer. Despite the common use of corticosteroids in psoriasis treatment, their limited efficacy and numerous side effects pose significant challenges. This research introduces a promising alternative approach by encapsulating eugenol (EU) in soya phosphatidylcholine (SPC) nanoparticles (EUNPs) which showed spherical shape nanoparticles with a hydrodynamic size of approximately 200 nm, polydispersity index 0.23, encapsulation efficiency of 85% having good colloidal stability indicated by ζ-potential of -27 mV. Later on, these EUNPs were formulated into a topical hydrogel system by using Carbopol 974P (EUNPGel), which exhibited superior drug loading, enhanced release kinetics for 48 h, long-term stability, and the ability to scavenge reactive oxygen species (ROS). Furthermore, EUNPs inhibited keratinocyte proliferation, induced apoptosis, and augmented the uptake of IL-6-mediated inflammation in human keratinocyte cells. Application of EUNPs-loaded gels (EUNPGel) to imiquimod-induced psoriatic lesions demonstrated effective dermal penetration, suppressed keratinocyte hyperplasia and restored epidermal growth. This led to a remarkable reduction in the Psoriasis Area and Severity Index (PASI) score from 3.75 to 0.5 within 5 days. This novel approach enhances ROS scavenging capacity, improves cellular uptake, facilitates skin penetration and retention, reduces the activity of hyperactive immune cells, and suggests potential applications for treating other immune-related disorders such as acne and atopic dermatitis.

P31 Modelling epidermal melanocytes behaviour during plaque psoriasis resolution

Abstract Introduction and aims Melanocytes in the human epidermis exist in the stratum basale at a ratio of 1 melanocyte to approximately 10 keratinocytes. They do not divide, even upon ultraviolet radiation stimulation, and do not appear to apoptose. In psoriasis, this melanocyte/keratinocyte ratio is retained, despite the enormous keratinocyte hyperplasia, inferring a commensurate expansion in melanocyte number. Therefore, here we investigate whether melanocyte number is altered following the reduction of keratinocytes upon treatment of psoriasis plaques with biologic therapy. Methods Matching lesional and nonlesional epidermis sets of patients (n = 4) at day 0 and after 4 and 12 weeks of treatment were compared with healthy controls. To assess the presence of apoptotic melanocytes, the terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay was performed. Immunohistochemistry with microphthalmia-associated transcription factor (melanocyte marker) and Ki-67 (proliferation marker) was used to assess melanocyte proliferation. Finally, melanocyte number per mm of basal layer and melanocyte/keratinocyte ratio were estimated by image analysis using ImageJ. Results Proliferating melanocytes were detected in nonlesional and lesional samples and in resolving plaques after 4 and 12 weeks of treatment but not in healthy epidermis. Melanocyte number per mm of basal layer was significantly higher in nonlesional than lesional sections compared with healthy controls (P < 0.01) suggesting that melanocyte expansion already occurs prior to lesion establishment, revealing early melanocyte deregulation. After 4 and 12 weeks of treatment the number of melanocytes in lesional and nonlesional sections was still significantly higher than controls (P < 0.05) and had not returned to normal despite the dramatic reduction in keratinocytes. The TUNEL assay did not detect evidence of melanocyte apoptosis. Conclusions This study shows that rare melanocyte proliferation occurs in nonlesional psoriasis skin and in resolving lesional skin. Given our inability to detect apoptotic melanocytes, it remains unclear how melanocyte numbers return to normal after plaque resolution These unique findings support a role for melanocytes in psoriasis pathogenesis and encourage further investigation.

Biomineralized in situ catalytic nanoreactor integrated microneedle patch for on demand immunomodulator supply to combat psoriasis.

The endogenous immunomodulator adenosine (ADO) was expected to be potentialized as an efficacious mediator to combat psoriasis. However, its efficacy is severely hindered by its poor metabolic stability and insufficient accumulation at the dermatological lesions. Methods: In this study, a biomineralized in situ catalytic nanoreactor was delicately customized by encapsulating ADO precursor (adenosine monophosphate, AMP) within the internal porous skeleton of zeolitic imidazolate framework-90, followed by the biomineralization of the AMP catabolic enzyme on the outer layer. The nanocrystals were then incorporated into a dissolving microneedles patch, which was designed to deliver drugs with precision into the cutaneous lesion and enhance the efficacy of psoriasis treatment. Results: Upon penetration into the skin, the nanoreactors were released and underwent a gradual collapse of their structure, releasing AMP when exposed to the acidic microenvironment. Meanwhile, the acidic pH could trigger an in situ catalytic reaction to continuously produce ADO. This system yielded remarkable results in a psoriasis-like mouse model. The mechanism study demonstrated that this system could substantially reshape the inflammatory ecosystem by inhibiting the keratinocyte hyperplasia, reducing inflammatory cytokine expression, and regulating the infiltration of immune cells. Conclusion: The in situ catalytic nanoreactor integrated microneedle patch is a promising modular platform for co-delivery of prodrugs and their catabolic enzymes, offering a potential solution for various diseases.

Alleviating psoriatic skin inflammation through augmentation of Treg cells via CTLA-4 signaling peptide.

Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role in psoriasis pathogenesis, while regulatory T (Treg) cells are diminished during psoriatic inflammation. Current psoriasis treatments largely focus on IL-17 and IL-23, however, few studies have explored therapeutic drugs targeting an increase of Treg cells to control immune homeostasis. In this study, we investigated the effects of a cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling peptide (dNP2-ctCTLA-4) in Th17, Tc17, γδ T cells, Treg cells in vitro and a mouse model of psoriasis. Treatment with dNP2-ctCTLA-4 peptide showed a significant reduction of psoriatic skin inflammation with increased Treg cell proportion and reduced IL-17 production by T cells, indicating a potential role in modulating psoriatic skin disease. We compared dNP2-ctCTLA-4 with CTLA-4-Ig and found that only dNP2-ctCTLA-4 ameliorated the psoriasis progression, with increased Treg cells and inhibited IL-17 production from γδ T cells. In vitro experiments using a T cell-antigen presenting cell co-culture system demonstrated the distinct mechanisms of dNP2-ctCTLA-4 compared to CTLA-4-Ig in the induction of Treg cells. These findings highlight the therapeutic potential of dNP2-ctCTLA-4 peptide in psoriasis by augmenting Treg/Teff ratio, offering a new approach to modulating the disease.

Ultraviolet B radiation-induced JPH203-loaded keratinocyte extracellular vesicles exert etiological interventions for psoriasis therapy

Psoriasis is a multifactorial immuno-inflammatory skin disease, characterized by keratinocyte hyperproliferation and aberrant immune activation. Although the pathogenesis is complex, the interactions among inflammation, Th17-mediated immune activation, and keratinocyte hyperplasia are considered to play a crucial role in the occurrence and development of psoriasis. Therefore, pharmacological interventions on the “inflammation-Th17-keratinocyte” vicious cycle may be a potential strategy for psoriasis treatment. In this study, JPH203 (a specific inhibitor of LAT1, which engulfs leucine to activate mTOR signaling)-loaded, ultraviolet B (UVB) radiation-induced, keratinocyte-derived extracellular vesicles (J@EV) were prepared for psoriasis therapy. The EVs led to increased interleukin 1 receptor antagonist (IL-1RA) content due to UVB irradiation, therefore not only acting as a carrier for JPH203 but also functioning through inhibiting the IL-1-mediated inflammation cascade. J@EV effectively restrained the proliferation of inflamed keratinocytes via suppressing mTOR-signaling and NF-κB pathway in vitro. In an imiquimod-induced psoriatic model, J@EV significantly ameliorated the related symptoms as well as suppressed the over-activated immune reaction, evidenced by the decreased keratinocyte hyperplasia, Th17 expansion, and IL17 release. This study shows that J@EV exerts therapeutic efficacy for psoriasis by suppressing LAT1-mTOR involved keratinocyte hyperproliferation and Th17 expansion, as well as inhibiting IL-1-NF-κB mediated inflammation, representing a novel and promising strategy for psoriasis therapy.

Non-IgE-reactive allergen peptides deteriorate the skin barrier in house dust mite-sensitized atopic dermatitis patients.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 cytokine-driven skin inflammation and epithelial barrier dysfunction. The latter is believed to allow the increased penetration of chemicals, toxins, and allergens into the skin. House dust mite allergens, particularly Der p 2, are important triggers in sensitized individuals with AD; the precise actions of these allergens in epithelial biology remain, however, incompletely understood. In this study, we compared the effects of the protein allergen Der p 2 and a mix of non-IgE-reactive Der p 2 peptides on skin cells using patch tests in AD patients and healthy participants. We then analyzed mRNA expression profiles of keratinocytes by single-cell RNA-sequencing. We report that existing barrier deficiencies in the non-lesional skin of AD patients allow deep penetration of Der p 2 and its peptides, leading to local microinflammation. Der p 2 protein specifically upregulated genes involved in the innate immune system, stress, and danger signals in suprabasal KC. Der p 2 peptides further downregulated skin barrier genes, in particular the expression of genes involved in cell-matrix and cell-cell adhesion. Peptides also induced genes involved in hyperproliferation and caused disturbances in keratinocyte differentiation. Furthermore, inflammasome-relevant genes and IL18 were overexpressed, while KRT1 was downregulated. Our data suggest that Der p 2 peptides contribute to AD initiation and exacerbation by augmenting hallmark features of AD, such as skin inflammation, barrier disruption, and hyperplasia of keratinocytes.

Deciphering the mechanism of PSORI-CM02 in suppressing keratinocyte proliferation through the mTOR/HK2/glycolysis axis.

Hyperplasia of epidermal keratinocytes that depend on glycolysis is a new hallmark of psoriasis pathogenesis. Our previous studies demonstrated that PSORI-CM02 could halt the pathological progression of psoriasis by targeting inflammatory response and angiogenesis, but its effect(s) and mechanism(s) on proliferating keratinocytes remained unclear. In this study, we aim to identify components of PSORI-CM02 that are absorbed into the blood and to determine the effect(s) of PSORI-CM02 on keratinocyte proliferation and its molecular mechanism(s). We used the immortalized human epidermal keratinocyte cell line, HaCaT, as an in vitro model of proliferating keratinocytes and the imiquimod-induced psoriasis mouse (IMQ) as an in vivo model. Metabolite profiles of vehicle pharmaceutic serum (VPS), PSORI-CM02 pharmaceutic serum (PPS), and water extraction (PWE) were compared, and 23 components of PSORI-CM02 were identified that were absorbed into the blood of mice. Both PPS and PWE inhibited the proliferation of HaCaT cells and consequently reduced the expression of the proliferation marker ki67. Additionally, PPS and PWE reduced phosphorylation levels of mTOR pathway kinases. Seahorse experiments demonstrated that PPS significantly inhibited glycolysis, glycolytic capacity, and mitochondrial respiration, thus reducing ATP production in HaCaT cells. Upon treatments of PPS or PWE, hexokinase 2 (HK2) expression was significantly decreased, as observed from the set of glycolytic genes we screened. Finally, in the IMQ model, we observed that treatment with PSORI-CM02 or BPTES, an inhibitor of mTOR signaling, reduced hyperproliferation of epidermal keratinocytes, inhibited the expression of p-S6 and reduced the number of proliferating cell nuclear antigen (PCNA)-positive cells in lesioned skin. Taken together, we demonstrate that PSORI-CM02 has an anti-proliferative effect on psoriatic keratinocytes, at least in part, by inhibiting the mTOR/HK2/glycolysis axis.

The Experimental Animal Models in Psoriasis Research: A Comprehensive Review.

Psoriasis is an autoimmune, chronic, inflammatory skin condition mediated by T cells. It differs from other inflammatory conditions by causing significant alterations in epidermal cell proliferation and differentiation that are both complicated and prominent. The lack of an appropriate animal model has significantly hindered studies into the pathogenic mechanisms of psoriasis since animals other than humans typically do not exhibit the complex phenotypic features of human psoriasis. A variety of methods, including spontaneous mutations, drug-induced mutations, genetically engineered animals, xenotransplantation models, and immunological reconstitution approaches, have all been employed to study specific characteristics in the pathogenesis of psoriasis. Although some of these approaches have been used for more than 50years and far more models have been introduced recently, they have surprisingly not yet undergone detailed validation. Despite their limitations, these models have shown a connection between keratinocyte hyperplasia, vascular hyperplasia, and a cell-mediated immune response in the skin. The xenotransplantation of diseased or unaffected human skin onto immune-compromised recipients has also significantly aided psoriasis research. This technique has been used in a variety of ways to investigate the function of T lymphocytes and other cells, including preclinical therapeutic studies. The design of pertinent in vivo and in vitro psoriasis models is currently of utmost concern and a crucial step toward its cure. This article outlines the general approach in the development of psoriasis-related animal models, aspects of some specific models, along with their strengths and limitations.

First report of Psittacid Avipoxvirus in Agapornis in Mexico

A postmortem study was performed on two lovebirds (Agapornis fischeri and Agapornis personatus) that had scabs in the periocular region and on the eyelid, as well as serous blepharitis. Microscopically, the eyelids showed ulcers, necrosis and serocellular crusts, severe hyperplasia of keratinocytes with eosinophilic intracytoplasmic inclusion bodies (Bollinger's bodies), bacterial colonies of gram-positive coccoid morphology and PAS-positive septate and 45° branching hyphae. The microbiological study identified the colonies as Staphylococcus spp. and Aspergillus fumigatus, respectively. Using molecular techniques, avian pox clade C was identified on the eyelid. This is the first report in Mexico of a case of avian pox in parrots associated with clade C Avipoxvirus

Mead acid inhibits retinol-induced irritant contact dermatitis via peroxisome proliferator-activated receptor alpha.

Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B4 production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.

Glutamine-Based Metabolism Normalization and Oxidative Stress Alleviation by Self-Assembled Bilirubin/V9302 Nanoparticles for Psoriasis Treatment.

Psoriasis is an immune-mediated chronic inflammatory skin disorder characterized by epidermal hyperplasia and infiltration of inflammatory cells. Even though the pathogenesis remains unclear, T helper 17 (Th17) cells-mediated inflammation and keratinocyte-involved proliferation are considered to play key roles during the occurrence and the development of psoriasis. Therefore, suppressing the infiltration/function of Th17 and the abnormal hyperplasia of keratinocytes can be a rational strategy for ameliorating and treating psoriasis. In this study, a self-assembly nanoparticle (BVn) is developed with bilirubin (an endogenous antioxidant) and V9302 (a blocker of ASCT2, an amino acid transporter mediating glutamine influx for providing energy and activating mammalian target of rapamycin [mTOR] pathway) to intervene the local metabolism and alleviate oxidative stress for psoriasis treatment. BVn effectively suppresses inflammatory keratinocyte proliferation and scavenges excess reactive oxygen species (ROS). In the in vivo psoriasis mouse model, BVn shows increased permeation and delayed retention in the psoriatic lesion and reverses the psoriasis-related symptoms, evidenced by the normalized keratinocyte condition and decreased Th17 infiltration/activation. Mechanism study indicates that BVn not only cut off the energy supply but also suppressed cell proliferation or lymph cell expansion by deactivating mTOR pathway, besides alleviated oxidative stress. BVn-based glutamine metabolism modulation strategy offers a promising strategy for psoriasis therapy.

LOWER LIP MELANOACANTHOMA MICROSCOPICALLY PRESENTING PLASMA CELL CHEILITIS–LIKE FEATURES

Oral melanoacanthoma is an uncommon benign pigmented lesion, microscopically presenting hyperplasia of spinous keratinocytes and dendritic melanocytes. Its pathogenesis remains uncertain, although the clinical behavior suggests a reactive origin. Oral melanoacanthoma affects mainly young adults and Blacks, with a strong female predilection. The most common oral sites are the buccal mucosa, lip, palate, and gingiva. Plasma cell cheilitis (PCC) is an inflammatory disorder of unknown etiology that affects the lips. The clinical presentation of PCC is variable, sometimes simulating malignancy, and microscopically characterized by a dense plasma cell infiltrate. Here, we present a 59-year-old Black male patient presenting blackish-colored lesions, associated with a reddish erosive area, on the lower lip, 1.5 years ago. Microscopy revealed melanoacanthoma associated with intense lymphoplasmacytic infiltrate, such as observed in PCC. If the current case represents a microscopic spectrum of melanoacanthoma or simultaneous presence of melanoacanthoma and PCC remains open to debate, however, we favor the former.

Violation of the skin barrier in patients with allergic dermatoses: causes, consequences, possibilities of correction

The article considers the topical dermatological issue concerning the breach of the integrity of the skin’s barrier in patients with allergic dermatosis. The horny layer of the skin in such patients can be broken as a result of numerous external causes: excoriations, injuries, allergens, irritants, etc. These factors, in turn, contribute to the activation of endogenous dermal proteases and decrease in the synthesis of epidermal lipids, which leads to reduced elasticity of corneocytes, increased intercellular spaces, and facilitates access for antigenic stimulants that promote the development of inflammation. The decrease in the skin’s barrier is accompanied by the development of immune inflammation, production of pro-inflammatory cytokines that inhibit the generation of antimicrobial factors, induce hyperplasia and apoptosis of keratinocytes. The integral approach plays a leading role in the treatment of the disease due to the specifics of the pathogenesis and course of allergic dermatoses. In the practice of a dermatologist, topical glucocorticosteroids occupy an important place. With their help, it is possible to quickly cope with the symptoms of inflammation in many dermatoses.The introduction presents current literature data on the role of skin ceramides in the restoration of the epidermal barrier. It is indicated that the epidermis of patients suffering from various dermatoses is characterized by a decrease in the production and dysfunction of physiological lipids, and, therefore, is prone to an increase in the incidence of pathological skin changes. Therefore, in allergic dermatoses, it is preferable to use products containing ceramides in their composition, which reduce transepidermal moisture loss, strengthen the structures of the epidermal barrier, and allow further elimination of relapses of the disease and improve the quality of life of patients.

Self-assembled nanoparticles with bilirubin/JPH203 alleviate imiquimod-induced psoriasis by reducing oxidative stress and suppressing Th17 expansion

Psoriasis is a chronic inflammatory skin disease with dysregulation of the immune system, which usually manifests as erythematous scleroma with hyperplasia of the epidermis. Although the pathogenesis remains unclear, oxidative stress and inflammation are inextricably linked during the development of psoriasis. Therefore, scavenging of ROS and suppression of inflammation may be a rational and effective strategy to ameliorate psoriasis and delay its further development. Here, a “Tanghulu”-like nanoplatform (BJN) is developed using the endogenous antioxidant bilirubin and a specific inhibitor (JPH203) of LAT1, an amino acid transporter involved in the activation of mTOR, for treatment of psoriasis by scavenging ROS and interfering with mTOR signaling, consequently blocking Th17 and IL-17 release. The nanoparticles show increased uptake in inflamed keratinocytes and display an efficient ROS scavenging capability. In an in vivo psoriasis model, BJN effectively permeate into the inflamed skin and be retained there, thereby reversing the psoriasis-specific changes in the imiquimod-induced mice as evident from suppression of keratinocyte hyperplasia and decrease in immune cell infiltration. This study shows that BJN can exert a superior anti-psoriasis effect by scavenging ROS, blocking the LAT1-mTOR pathway, inactivating immune reaction, restricting Th17 differentiation, and decreasing IL-17A secretion, offering a promising strategy for psoriasis treatment.

215 Unambiguous evidence of melanocyte proliferation in plaque psoriasis

Melanocytes of the human epidermis are located in the stratum basale in a ratio of 1 melanocyte to 10 keratinocytes. Melanocytes do not divide in healthy epidermis, even after UVR stimulation. While psoriasis is characterised by keratinocyte hyperplasia, pigmentary anomalies can occur (hypopigmented Woronoff ring, hyperpigmentation). Curiously, the normal s.basale melanocyte to keratinocyte ratio is retained in the hyperplastic epidermis. This may infer a commensurate (compensatory) expansion in melanocyte number.

247 Epidermal aPKC polarity signaling suppresses field cancerization upon loss of p53

Squamous cell carcinoma of the skin often arise in areas of field cancerization but the molecular mechanisms that promote field cancerization and transition to invasive tumors is still poorly understood. Although P53 mutations are linked to field cancerization, epidermal p53 inactivation in mice is not sufficient to induce field cancerization. We previously showed that the atypical protein kinase Cι (aPKCι) regulates cell polarity and skin stem cell dynamics, and promotes skin cancer in a DMBA/TPA model. Surprisingly, combined epidermal deletion of aPKCι and p53 (edko) in mice promotes field cancerization and tremendously accelerates squamous cell carcinomas (SCC) formation when compared to p53 loss alone. In human SCCs low epidermal aPKC levels also correlate with poor prognosis for metastasis-free survival, thus identifying a conserved tumor suppressive role for aPKC in skin cancer. By combining RNA Seq with immunofluorescence analysis we found that at postnatal day (P) 21, when proliferation is already increased but without obvious changes yet in edko epidermal architecture, combined loss of aPKCι and p53 creates an inflammatory and hypoxic microenvironment resulting in a 10-fold increase in macrophage numbers. Importantly, depleting macrophages prevented dysplastic keratinocyte hyperplasia and restored epidermal architecture. Molecularly, loss of aPKC/P53 activates epidermal Stat3, which in vivo is essential for hypoxia and macrophage infiltration and drives hyperplasia of dysplastic keratinocytes and SCC. Thus, our results identify epidermal polarity signaling as a gatekeeper of the tumor microenvironment to prevent field cancerization and widespread SCC upon loss of p53.

E3 ubiquitin ligase NEDD4L negatively regulates keratinocyte hyperplasia by promoting GP130 degradation.

Psoriasis is mainly characterized by abnormal hyperplasia of keratinocytes and immune cells infiltrating into the dermis and epidermis. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is a highly conserved HECT type E3 ligase that plays an important role in regulating physiological and pathological processes. Here, we identify NEDD4L as a negative regulator of psoriasis. Nedd4l significantly inhibits imiquimod (IMQ)-induced skin hyperplasia, and this effect is attributed to the inhibitory effect of NEDD4L on IL-6/GP130 signaling in keratinocytes. Mechanistically, NEDD4L directly interacts with GP130 and mediates its Lys-27-linked ubiquitination and proteasomal degradation. Moreover, the expression of NEDD4L is downregulated in the epidermis from IMQ-treated mice and psoriasis patients and negatively correlates with the protein levels of GP130 and p-STAT3 in clinical samples. Collectively, we uncover an inhibitory role of NEDD4L in the pathogenesis of psoriasis and suggest a new therapeutic strategy for the treatment of psoriasis.

Oral melanoacanthoma: Case report with review of literature

Oral melanoacanthoma is a rare, benign pigmented lesion that presents most commonly on the buccal mucosa. It is characterized clinically by the sudden appearance and rapid growth of a macular brown-black lesion and histologically by hyperplasia of spinous keratinocytes and dendritic melanocytes. We report a case of oral melanoacanthoma in a 37-year-old Indian male, who presented with an intra-oral brown macular lesion on the right buccal mucosa with a duration of ten days. Microscopic examination revealed acanthosis of stratified squamous surface epithelium with dendritic melanocytes in the basal and suprabasal layers and presence of melanophages in the underlying connective tissue. Based on the history, clinical features and histological presentation, the lesion was diagnosed as oral melanoacanthoma. Keywords: Melanocytes, Melanoacanthoma, Dendritic

Toe Absence Related to Verrucous Carcinoma

Abstract Introduction: Verrucous carcinoma is a rare variant of squamous cell carcinoma. It generally grows exogenously and bone erosion is rare. Here we present a case of verrucous carcinoma on the foot with toe absence. Case presentation: A 64-year-old man presented with a 6-year history of a slowly growing exogenous hyperkeratotic verrucous lesion on the right fifth toe, which had been absent for 1 year. Before the lesion appeared, he had undergone nail extraction on this toe. The culture of fungi and mycobacteria were negative. Three-dimensional computed tomography showed that the fifth toe of the right foot was absent. Histopathological examination showed that the lesion was exogenous and verrucous and exhibited moderate keratinocyte hyperplasia. Combined with clinical manifestation and histopathological examination, verrucous carcinoma is suggested. The lesion was surgically excised, and the patient was followed up for more than 6 months without recurrence. Discussion: Verrucous carcinoma is an exophytic tumor with verrucous growth at the beginning, which can invade deep tissues and even cause limb mutilation. When encountering a patient with a wart-like plaque on the foot that responds poorly to conventional treatments, clinicians should maintain a high degree of clinical vigilance and a low threshold for biopsy. Conclusion: We observed a rare outcome of toe absence associated with verrucous carcinoma. Therefore, early diagnosis of verrucous carcinoma is very important. Surgical excision is an effective treatment at present. Extensive resection is usually required to avoid recurrence.