Lysophosphatidic Acid Mediates Imiquimod-Induced Psoriasis-like Symptoms by Promoting Keratinocyte Proliferation through LPAR1/ROCK2/PI3K/AKT Signaling Pathway.

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.

Small intestinal immune-environmental changes induced by oral tolerance inhibit experimental atopic dermatitis.

Atopic dermatitis is a chronic skin inflammatory disease mediated by Th2-type immune responses. Although intestinal immune responses have been shown to play a critical role in the development or prevention of atopic dermatitis, the precise influence of intestinal immunity on atopic dermatitis is incompletely understood. We show here that orally tolerized mice are protected from experimental atopic dermatitis induced by sensitization and epicutaneous (EC) challenge to ovalbumin. Although the expression of Th2-type cytokines in the small intestine of orally tolerized and EC-challenged mice did not change significantly, these mice showed decreased inflammatory responses in the small intestine with restoration of microbial change elicited by the EC challenge. Interestingly, an increase in small intestinal eosinophils was observed with the EC challenge, which was also inhibited by oral tolerance. The role of small intestinal eosinophils and microbiota in the pathogenesis of experimental atopic dermatitis was further substantiated by decreased inflammatory mediators in the small intestine and attenuated Th2-type inflammation in the skin of eosinophil-deficient and microbiota-ablated mice with EC challenges. Based on these data, we propose that the bidirectional interaction between the skin and the intestine has a role in the pathogenesis of atopic dermatitis and that modulation of the intestinal microenvironments could be a therapeutic approach to atopic dermatitis.

A basophil-neuronal axis promotes itch.

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.

Associations between ambient air pollution and medical care visits for atopic dermatitis.

BACKGROUND: Previous studies have reported numerous environmental factors for atopic dermatitis (AD), such as allergens and chemical stimulants. However, few studies have addressed the relationship between ambient air pollution and AD at a population level. OBJECTIVE: To evaluate the effect of air pollutants on medical care visits for AD and to identify susceptible populations. METHODS: In this time-series study conducted on 513,870 medical care visits for AD from 2012 to 2015 identified by reviewing national health insurance claim data in Incheon, Republic of Korea. Treating daily number of medical care visits for AD as a dependent variable, generalized additive models with Poisson distributions were constructed, which included air pollutant levels, ambient temperature, relative humidity, day of the week, national holiday, and season. Risks were expressed as relative risks (RR) with 95% confidence intervals (95% CIs) per interquartile range increase of each air pollutant. RESULTS: Higher levels of particulate matter of diameter ≤10 µm (PM10) (RR, 1.009; 95% CI, 1.007-1.012), ozone (1.028; 1.023-1.033), and sulfur dioxide (1.033; 1.030-1.037) were significantly associated with increased risk of medical care visits for AD on same days. In all age and sex groups, ozone was associated with a significantly higher risk of medical care visits, with the greatest risk among 13- to 18-year-old males (RR, 1.127; 95% CI, 1.095-1.159). CONCLUSION: This study suggests relationships of ambient PM10, ozone, and sulfur dioxide levels with medical care visits for AD.

Cutaneous lupus erythematosus and its association with systemic lupus erythematosus: A nationwide population-based cohort study in Korea.

Although lupus erythematosus is known to be more common among women of color, the study populations in previous reports were predominantly Caucasian and there is scarce information on Asian patients. Therefore, we performed a retrospective study using a nationwide population-based cohort in South Korea. The average annual incidence of cutaneous lupus was 4.36/100 000. Among 634 patients with cutaneous lupus, 20.8% had systemic disease: cutaneous lupus was diagnosed before systemic lupus in 4.26% and after systemic lupus in 8.52%. More female patients than male patients developed systemic lupus erythematosus. The average time to progression to systemic lupus was 1.53 ± 1.46 years.

Optimization of Cytokine Milieu to Reproduce Atopic Dermatitis-related Gene Expression in HaCaT Keratinocyte Cell Line.

Although atopic dermatitis (AD) is characterized by cytokine production predominantly mediated by T helper (Th) 2 cells, AD pathogenesis also involves innate immune and Th1 cells. To optimize the cytokine milieu required for accurate reproduction of AD-related gene expression profile in vitro, we evaluated the expression pattern of CCL22, CCL17, IL5, IL13, IL33, IL25, TSLP, FLG, and LOR in human lesional AD skin and cytokine-stimulated HaCaT cells. An increase in Th2 mediators (IL5, IL13, CCL22, CCL17, IL25, IL33, and TSLP) and a decrease in genes related to cornified cell envelope (filaggrin and loricrin) were observed in human AD lesions. Innate (tumor necrosis factor-α) and/or Th1/Th2 adaptive cytokines (interferon-γ/IL-4) were required for inducing these inflammatory changes in HaCaT cells, implying that a complex network of innate, Th1, and Th2 cytokines drives AD-like changes. Therefore, stimulation with various combinations of cytokines, beyond Th2 polarization, is necessary when HaCaT cell line is used to study genetic changes implicated in AD pathogenesis.

Cholesterol Clefts in Basal Cell Carcinoma: An Under-Recognized Association.

Cholesterol clefts have rarely been described in cutaneous tumors other than lipid-rich tumors. However, they seem to be a relatively common phenomenon in basal cell carcinoma (BCC). This study was undertaken to determine the frequency of cholesterol cleft deposition in BCCs, and to identify associated histopathologic and clinical features. Twenty-eight of 249 BCC cases reviewed showed features of cholesterol cleft. Mean disease duration in those with cholesterol cleft was significantly longer than in those without cholesterol cleft (5.58 vs. 3.29 years, respectively; P = 0.013). Sex and age distributions, and average tumor longest diameter (11.6 vs. 9.41 mm) were no different for those with or without cholesterol clefts. The most common anatomical location was the nose in both those with and without cholesterol clefts. BCCs without cholesterol clefts more frequently involved the periauricular and perioral areas, and areas other than the head and neck, such as the trunk and lower extremities (P = 0.087). Histopathologic features of necrosis (26/28, 92.86%), keratinization (19/28, 67.86%), and pigment deposition (18/28, 64.29%) were found to be associated with cholesterol clefts. Cholesterol clefts were intratumorally located in 27/28 cases (96.43%), and stromally located in 2 cases (7.14%); intravascularly located cholesterol clefts were observed in no case. In conclusion, this study shows that cholesterol clefts are relatively common in BCC, and suggests that cholesterol crystal deposition could be associated with longer disease duration and microtrauma.

A Possible Case of Statin-Induced Ichthyosis in an Elderly Woman.

Ichthyosis is a heterogeneous group of hereditary or acquired skin disorders, characterized by increased stratum corneum production. Several systemic diseases and many drugs can occasionally cause acquired ichthyosis. We report a case of statin-induced ichthyosis in which the causality between statin and ichthyosis was found possible by using the Naranjo scale. A 79-year-old woman presented with pruritic skin lesions on both legs that appeared erythematous, scaly, and cracked. A clinical diagnosis of acquired ichthyosis was made and the statin was suspected as the cause. The skin lesions improved after 6 weeks of dose reduction of the statin.

Oxidative stress and antioxidant strategies in dermatology.

Oxidative stress results from a prooxidant-antioxidant imbalance, leading to cellular damage. It is mediated by free radicals, such as reactive oxygen species or reactive nitrogen species, that are generated during physiological aerobic metabolism and pathological inflammatory processes. Skin serves as a protective organ that plays an important role in defending both external and internal toxic stimuli and maintaining homeostasis. It is becoming increasingly evident that oxidative stress is involved in numerous skin diseases and that antioxidative strategies can serve as effective and easy methods for improving these conditions. Herein, we review dysregulated antioxidant systems and antioxidative therapeutic strategies in dermatology.

Treatment of patients with refractory atopic dermatitis sensitized to house dust mites by using sublingual allergen immunotherapy.

Even though atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, its treatment remains a challenge in clinical practice, with most approaches limited to symptomatic, unspecific anti-inflammatory, or immunosuppressive treatments. Many studies have shown AD to have multiple causes that activate complex immunological and inflammatory pathways. However, aeroallergens, and especially the house dust mite (HDM), play a relevant role in the elicitation or exacerbation of eczematous lesions in many AD patients. Accordingly, allergen-specific immunotherapy has been used in AD patients with the aim of redirecting inappropriate immune responses. Here, we report three cases of refractory AD sensitized to HDM who were treated with sublingual immunotherapy.

Analysis of the prevalence of and risk factors for atopic dermatitis using an ISAAC questionnaire in 8,750 Korean children.

BACKGROUND: Since 1995, epidemiologic studies of atopic disorders using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire have been performed in many countries, including the Republic of Korea. The prevalence, burden and risk factors of atopic dermatitis were surveyed in these studies, which helped to enhance their comparability among different areas and age groups, as well as to clarify the nature of atopic dermatitis and other atopic disorders. METHODS: From 21 facilities, 8,750 children were enrolled in this cross-sectional study. The data were collected via the Internet using a questionnaire based on the Korean-language version of the ISAAC study format. RESULTS: The prevalence of atopic dermatitis over the previous 12 months was 14.4%. The prevalence in preschool children was significantly higher than in elementary school children. Family history of atopic diseases, diagnosis of allergic conjunctivitis and diagnosis of food allergy were positively associated with atopic dermatitis in both preschool and elementary school children. In addition, raising pets was positively associated with atopic dermatitis in preschool children. In elementary school children, female gender, secondhand smoking, breastfeeding, changing the parents' house to a newly built one during the first year of life, diagnosis of asthma and diagnosis of allergic rhinitis were positively associated with atopic dermatitis. CONCLUSION: The prevalence of atopic dermatitis in preschool and elementary school children in Korea is similar to that of children in other developing countries. The risk factors for atopic dermatitis are different in preschool and elementary school children. More detailed strategies will be necessary to reduce atopic dermatitis in both age groups.

Assessment of an imiquimod-induced psoriatic mouse model in relation to oxidative stress.

Psoriasis is a chronic inflammatory skin disease that is thought to be related to oxidative stress. Much progress has been made in understanding the pathophysiology of psoriasis in relation to the immunologic and antioxidant systems. However, this progress has been hindered by the lack of an appropriate animal model for psoriasis. Recently, imiquimod (IQM)-induced psoriasis-like cutaneous inflammation has been reported in mice and humans. We verified the usefulness of an IQM-induced mouse model in relation to the antioxidant system. BALB/C female mice at 8-10 weeks of age were treated with IQM cream in this study. We analyzed clinical and histopathological changes. Increased reactive oxygen species production was measured by glutathione assay. Levels of myeloperoxidase (MPO) and superoxide dismutase-1 (SOD1) were determined by western blotting and immunohistochemical analyses. The activity of SOD was measured by a SOD activity assay kit. Application of IQM-induced skin inflammation similar to psoriasis in clinical and histopathological aspects. Accumulation of immune cells was confirmed. Oxidative stress was increased, the antioxidant enzyme MPO levels were increased, and both SOD levels and activity were decreased. In conclusion, the IQM-induced mouse model showed an aberrant antioxidant system. Levels of MPO and oxidative stress were increased, and the level and activity of SOD were decreased. Since this model seemed to be an appropriate model for psoriasis, it can be used to further study the pathogenic role of redox imbalance in psoriasis.

Chromoblastomycosis Caused by Phialophora richardsiae.

Chromoblastomycosis is a chronic fungal disease of the skin and subcutaneous tissues caused by a group of dematiaceous (black) fungi. The most common etiologic agents are Fonsecaea pedrosoi and Cladophialophora carrionii, both of which can be isolated from plant debris. The infection usually follows traumatic inoculation by a penetrating thorn or splinter wound. Several months after the injury, painless papules or nodules appear on the affected area; these papules then progress to scaly and verrucose plaques. We report a case of chromoblastomycosis caused by Phialophora richardsiae, which has been rarely associated with chromoblastomycosis. The case involved a 43-year-old male, who for the past 2 months had noted an erythematous, pustulous plaque that was somewhat dark brown in color on his right shin; the plaque also had intermittent purulent discharge and crust formation. On histopathological examination, chronic granulomatous inflammation and sclerotic cells were seen. The tissue fungus culture grew out the typical black fungi of P. richardsiae, which was confirmed by polymerase chain reaction. The patient has been treated with a combination of terbinafine and itraconazole for 3 months with a good clinical response.