Analysis of aquaporin 9 expression in human epidermis and cultured keratinocytes.

Aquaporin 9 (AQP9) is a member of the aquaglyceroporin family that transports glycerol, urea and other small solutes as well as water. Compared to the expression and function in epidermal keratinocytes of AQP3, another aquaglyceroporin, our knowledge of epidermal AQP9 remains elusive. In this study, we investigated the expression of AQP9 in the human epidermis and cultured keratinocytes. Immunofluorescence studies revealed that AQP9 expression is highly restricted to the stratum granulosum of the human epidermis, where occludin is also expressed at the tight junctions. Interestingly, the AQP3 staining decreased sharply below the cell layers in which AQP9 is expressed. In cultured normal human epidermal keratinocytes (NHEK), knock-down of AQP9 expression in the differentiated cells induced by RNA interference reduced glycerol uptake, which was not as pronounced as was the case with AQP3 knock-down cells. In contrast, similar reduction of urea uptake was detected in AQP9 and AQP3 knock-down cells. These findings suggested that AQP9 expression in NHEK facilitates at least the transport of glycerol and urea. Finally, we analyzed the effect of retinoic acid (RA), a potent stimulator of keratinocyte proliferation, on AQP3 and AQP9 mRNA expression in differentiated NHEK. Stimulation with RA at 1 µM for 24 h augmented AQP3 expression and down-regulated AQP9 expression. Collectively, these results indicate that AQP9 expression in epidermal keratinocytes is regulated in a different manner from that of AQP3.

Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production.

Pellagra is a photosensitivity syndrome characterized by three "D's": diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

A double dose of levocetirizine leads to better control of histamine-induced flare, wheal and itch in healthy donors.

Levocetirizine is classified as a nonsedating second-generation antihistamine. This drug is used to treat allergic disorders such as urticaria and pruritus. Thus far, studies have demonstrated an increase in efficacy for refractory urticaria by increasing doses of antihistamines; however, more lines of supportive evidence for these guidelines are required to justify this management strategy. In this study, we found that a double dose of levocetirizine suppressed histamine-induced flare formation more rapidly and sustainably, and wheal and itch more extensively, compared with the conventional dose using both visual and laser Doppler imaging scales in a noninvasive manner. These results suggest that double-dosed levocetirizine treatment suppresses histamine-induced skin symptoms more rapidly, profoundly and sustainably than conventionally dosed levocetirizine treatment.

Reduction of Skin pH during Treatment for Palmoplantar Hyperhidrosis: A Conjecture on the Role of pH-Regulated Water Channel, i.e. Aquaporin.

Primary palmoplantar hyperhidrosis (PPH) is a disorder that involves excessive sweating on the palms and soles. Although the pathophysiology of PPH remains unknown, some treatments, including topical aluminum chloride (AC) and tap water iontophoresis (TWI), are effective at suppressing the perspiration. Herein, we report the kinetics of the skin pH of two cases of PPH treated with AC and TWI. We found that the skin pH decreased in accordance with the reduction in sweating. This finding indicates that the reduction in sweating may be attributed to the reduction of skin pH in AC and TWI. Whether or not the pH-regulated function of aquaporin can explain this finding remains unknown.

Normal immunostaining pattern for aquaporin-5 in the lesions of palmoplantar hyperhidrosis.

Aquaporin-5 (AQP-5) is a water-transporting protein expressed in mammal sweat glands. It has been reported that the expression of AQP-5 is involved in sweating of mice, rats, and horses. However, the physiological function of human AQP-5 is still uncertain. In this report, we examined the expression pattern of AQP-5 in the skin lesions of palmoplantar hyperhidrosis in patients with Nagashima-type palmoplantar hyperkeratosis (PPK). We found that there was no significant difference in AQP-5 expression in the palmoplantar skin of healthy subjects and patients with palmoplantar hyperhidrosis. Our findings suggest that a mechanism other than AQP-5 may be involved in the pathogenesis of hyperhidrosis in PPK.

Evaluation of basophil infiltration into the skin lesions of tick bites.

Recently, it has been described that basophils play an essential role in antibody-mediated acquired immunity against ticks in mice. However, it is still unknown whether basophil infiltration has any significance in the infestation with ticks in humans. In this report, we have evaluated the infiltration of basophils into human skin lesions of tick bites.

Comparison of the efficacy of fexofenadine 120 and 240 mg/day on chronic idiopathic urticaria and histamine-induced skin responses in Japanese populations.

BACKGROUND: H1-antihistamines are the first-line treatment of chronic idiopathic urticaria (CIU), but CIU is occasionally refractory to the conventional treatment doses. Guidelines in Europe recommend increasing doses as second-line therapy; however, more supportive evidences for these guidelines are required to justify this management strategy. METHODS: In this study, the authors evaluated the effect of conventional and double doses of fexofenadine HCl on CIU and on histamine-induced skin responses by iontophoresis using visual and laser Doppler imaging scales in healthy donors. RESULTS: Cutaneous manifestations in CIU and histamine-induced flare and itch in healthy donors were attenuated more extensively by a double dose of fexofenadine HCl compared with a conventional dose. CONCLUSION: The above findings support the management strategy that increasing the dose of non-sedative antihistamines is the second-line treatment choice for refractory CIU even in Japanese populations.

Epidermal phospholipase Cδ1 regulates granulocyte counts and systemic interleukin-17 levels in mice.

Phospholipase C is a key enzyme in phosphoinositide turnover. Although its functions have been extensively studied at the cellular level, many questions remain concerning its functions at the organ and individual animal levels. Here we demonstrate that mice lacking phospholipase Cδ1 develop granulocytosis associated with elevated serum levels of the granulopoietic cytokine interleukin-17. Re-introduction of phospholipase Cδ1 into keratinocytes of phospholipase Cδ1-deficient mice reverses this phenotype, whereas conditional ablation of phospholipase Cδ1 in keratinocytes recreates it. Interleukin-17 and its key upstream regulator interleukin-23 are also upregulated in epidermis. Loss of phospholipase Cδ1 from keratinocytes causes features of interleukin-17-associated inflammatory skin diseases. Phospholipase Cδ1 protein is downregulated in the epidermis of human psoriatic skin and in a mouse model of psoriasis. These results demonstrate that phosphoinositide turnover in keratinocytes regulates not only local inflammatory responses but also serum cytokine levels and systemic leukocyte counts, and affects distant haematopoietic organs.

PGD2 induces eotaxin-3 via PPARγ from sebocytes: a possible pathogenesis of eosinophilic pustular folliculitis.

BACKGROUND: Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis characterized by massive eosinophil infiltrates involving the pilosebaceous units. Recently, EPF has been regarded as an important clinical marker of HIV infection, and its prevalence is increasing in number. The precise mechanism by which eosinophils infiltrate into the pilosebaceous units remains largely unknown. Given that indomethacin, a COX inhibitor, can be successfully used to treat patients with EPF, we can assume that COX metabolites such as prostaglandins (PGs) are involved in the etiology of EPF. OBJECTIVE: To determine the involvement of PGs in the pathogenesis of EPF. METHODS: We performed immunostaining for PG synthases in EPF skin lesions. We examined the effect of PGD(2) on induction of eotaxin, a chemoattractant for eosinophils, in human keratinocytes, fibroblasts, and sebocytes and sought to identify its responsible receptor. RESULTS: Hematopoietic PGD synthase was detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD(2) was produced in the lesions. In addition, PGD(2) and its immediate metabolite 15-deoxy-Δ 12,14-PGJ(2) (15d-PGJ(2)) induced sebocytes to produce eotaxin-3 via peroxisome proliferator-activated receptor gamma. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of the EPF lesions. CONCLUSION: The PGD(2)/PGJ(2)-peroxisome proliferator-activated receptor gamma pathway induces eotaxin production from sebocytes, which may explain the massive eosinophil infiltrates observed around pilosebaceous units in EPF.

Upregulation of aquaporin-3 is involved in keratinocyte proliferation and epidermal hyperplasia.

Aquaporin-3 (AQP3) is a water/glycerol-transporting protein expressed in keratinocytes of the epidermis. We previously showed that AQP3-mediated transport of water and glycerol is involved in keratinocyte migration and proliferation, respectively. However, the involvement of AQP3 in epidermal hyperplasia in skin diseases, such as atopic dermatitis (AD), is unknown. In this study, we found significantly increased AQP3 transcript and protein expression in the epidermis of human AD lesions. The upregulation of AQP3 expression in human keratinocytes by transfection with human AQP3 DNA plasmid was associated with increased cellular glycerol and ATP, as well as increased cell proliferation. Among several cytokines and chemokines produced in the skin, CCL17, which is highly expressed in AD, was found to be a strong inducer of AQP3 expression and enhanced keratinocyte proliferation. In mouse AD models, AQP3 was strongly overexpressed in the epidermis in wild-type mice. Epidermal hyperplasia was reduced in AQP3-deficient mice, with a decreased number of proliferating keratinocytes. These results suggest the involvement of AQP3 in epidermal hyperplasia by a mechanism involving upregulated AQP3 expression and consequent enhancement of keratinocyte proliferation.

Large cell transformation mimicking regional lymphomatoid papulosis in a patient with mycosis fungoides.

A 57-year-old Japanese man with tumor-stage mycosis fungoides suddenly presented multiple small papules on the right chest. Histopathology of a biopsy specimen from the papules revealed medium-to-large pleomorphic lymphoid cells throughout the entire dermis but not in the epidermis, and the large cells expressed CD30 antigen. These newly-developed papules underwent spontaneous remission in the following 3 months. We reviewed the reported cases of mycosis fungoides, which showed CD30-positive large cell transformation and those of CD30-positive lymphoproliferative disorders associated with mycosis fungoides.

Late-onset self-healing reticulohistiocytosis: pediatric case of Hashimoto-Pritzker type Langerhans cell histiocytosis.

An 8-year-old otherwise healthy girl presented with a 3-month history of multiple asymptomatic, reddish-brown papules over the face and upper limbs. Histopathological and immunohistochemical examinations demonstrated an infiltrate of mononuclear cells containing abundant histiocytic cells in the dermis, and microabscess-like accumulation of the histiocytic cells in the epidermis. The histiocytic cells were positive for antibodies against S-100 protein and CD1a, but negative for anti-CD68. Lag and anti-langerin monoclonal antibodies reacted more weakly with these histiocytic cells than with Langerhans cells in the surrounding epidermis. The skin lesions spontaneously regressed within the following 3 months, and neither systemic involvement nor local recurrence was observed during the next 10 months. This case should be categorized as congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker), although the onset was not early in life.