Advanced Glycation End Products and Activation of Toll-like Receptor-2 and -4 Induced Changes in Aquaporin-3 Expression in Mouse Keratinocytes.

Prolonged inflammation and impaired re-epithelization are major contributing factors to chronic non-healing diabetic wounds; diabetes is also characterized by xerosis. Advanced glycation end products (AGEs), and the activation of toll-like receptors (TLRs), can trigger inflammatory responses. Aquaporin-3 (AQP3) plays essential roles in keratinocyte function and skin wound re-epithelialization/re-generation and hydration. Suberanilohydroxamic acid (SAHA), a histone deacetylase inhibitor, mimics the increased acetylation observed in diabetes. We investigated the effects of TLR2/TLR4 activators and AGEs on keratinocyte AQP3 expression in the presence and absence of SAHA. Primary mouse keratinocytes were treated with or without TLR2 agonist Pam3Cys-Ser-(Lys)4 (PAM), TLR4 agonist lipopolysaccharide (LPS), or AGEs, with or without SAHA. We found that (1) PAM and LPS significantly upregulated AQP3 protein basally (without SAHA) and PAM downregulated AQP3 protein with SAHA; and (2) AGEs (100 µg/mL) increased AQP3 protein expression basally and decreased AQP3 levels with SAHA. PAM and AGEs produced similar changes in AQP3 expression, suggesting a common pathway or potential crosstalk between TLR2 and AGEs signaling. Our findings suggest that TLR2 activation and AGEs may be beneficial for wound healing and skin hydration under normal conditions via AQP3 upregulation, but that these pathways are likely deleterious in diabetes chronically through decreased AQP3 expression.

Loss of Indoleamine-2,3-Dioxygenase-1 (IDO1) in Knockout Mice Does Not Affect the Development of Skin Lesions in the Imiquimod-Induced Mouse Model of Psoriasis.

Indoleamine-2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan resulting in tryptophan depletion and the accumulation of catabolites such as kynurenine. The expression/activity of IDO in various cells, including macrophages and dendritic cells, results in an inhibition of T-cell responses in a number of situations, such as toward allogeneic fetuses and tissue grafts. Psoriasis is an immune-mediated skin disease involving T cells; kynureninase and its generation of catabolites downstream of IDO are reported to play an important role in this disease. We hypothesized that mice lacking the IDO1 gene would exhibit a hyperactive immune response and an exacerbation of skin lesions in the imiquimod-induced mouse model of psoriasis. Littermate wild-type and IDO1-knockout mice were treated with imiquimod for 5 days, and the severity of psoriasiform skin lesions assessed using the psoriasis area and severity index (PASI), ear edema measured using a digital caliper, and thickness of the epidermis determined by histology. Expression of pro-inflammatory mediators and tryptophan-metabolizing enzymes was monitored using quantitative RT-PCR. Imiquimod increased ear edema, PASI scores, and epidermal thickness in both WT and IDO1 knockout mice; however, there were no differences observed between the 2 genotypes. There were also no differences in imiquimod's induction of skin inflammatory mediators, indicating no effect of IDO1 gene loss in this psoriasis model. Although these data suggest a lack of involvement of IDO1 in psoriatic skin inflammation, other possible mechanisms, such as compensatory changes in other pathways and the involvement of the IDO2 isoform, must also be considered.

Glycerol Improves Skin Lesion Development in the Imiquimod Mouse Model of Psoriasis: Experimental Confirmation of Anecdotal Reports from Patients with Psoriasis.

Glycerol is used in many skin care products because it improves skin function. Anecdotal reports by patients on the National Psoriasis Foundation website also suggest that glycerol may be helpful for the treatment of psoriasis, although to date no experimental data confirm this idea. Glycerol entry into epidermal keratinocytes is facilitated by aquaglyceroporins like aquaporin-3 (AQP3), and its conversion to phosphatidylglycerol, a lipid messenger that promotes keratinocyte differentiation, requires the lipid-metabolizing enzyme phospholipase-D2 (PLD2). To evaluate whether glycerol inhibits inflammation and psoriasiform lesion development in the imiquimod (IMQ)-induced mouse model of psoriasis, glycerol's effect on psoriasiform skin lesions was determined in IMQ-treated wild-type and PLD2 knockout mice, with glycerol provided either in drinking water or applied topically. Psoriasis area and severity index, ear thickness and ear biopsy weight, epidermal thickness, and inflammatory markers were quantified. Topical and oral glycerol ameliorated psoriasiform lesion development in wild-type mice. Topical glycerol appeared to act as an emollient to induce beneficial effects, since even in PLD2 knockout mice topical glycerol application improved skin lesions. In contrast, the beneficial effects of oral glycerol required PLD2, with no improvement in psoriasiform lesions observed in PLD2 knockout mice. Our findings suggest that the ability of oral glycerol to improve psoriasiform lesions requires its PLD2-mediated conversion to phosphatidylglycerol, consistent with our previous report that phosphatidylglycerol itself improves psoriasiform lesions in this model. Our data also support anecdotal evidence that glycerol can ameliorate psoriasis symptoms and therefore might be a useful therapy alone or in conjunction with other treatments.

Phosphatidylglycerol Inhibits Toll-Like Receptor-Mediated Inflammation by Danger-Associated Molecular Patterns.

Psoriasis is a common skin disorder characterized by hyperproliferation and aberrant differentiation of epidermal keratinocytes and inflammation. We previously showed that phosphatidylglycerol (PG) can regulate keratinocyte function and suppress skin inflammation. Based on data suggesting that PG can inhibit toll-like receptor (TLR) activation induced by microorganisms and their components, we determined whether PG can inhibit TLR activation in response to antimicrobial peptides. These peptides, which are up-regulated in psoriasis, are known to function as danger-associated molecular patterns (i.e., DAMPs) to activate TLRs and the innate immune system. Because S100A9 is elevated in psoriatic skin and in animal models of psoriasis, we selected S100A9 as a representative antimicrobial peptide DAMP. We showed that in primary keratinocytes and a macrophage cell line, PG suppressed inflammatory mediator production induced by recombinant S100A9 functioning through both TLR2 and TLR4. In addition, PG, but not phosphatidylcholine, inhibited downstream S100A9-elicited TLR2 and NF-κB activation. These results, to our knowledge previously unreported, show PG's ability to inhibit DAMP-induced TLR activation, thereby reducing inflammatory signals. In addition, topical PG ameliorated skin lesions and inflammation in a mouse model of psoriasis. Together, these results suggest the possibility of developing PG as a therapy for psoriasis.

High Sensitivity C-Reactive Protein Level and Psoriasis Severity in Thai Patients.

Background: Psoriasis vulgaris severity have been widely assessed by psoriasis area severity index (PASI) score. However, it may not be not the best measure because of the high variability and inability to tell the other aspect of the disease including co-morbidity and cardiovascular risk. Objective: To determine the correlation between high sensitivity C-reactive protein (hs-CRP) level and psoriasis severity and to determine co-morbidities of psoriasis patients. Material and Method: One hundred eighty psoriasis patients and thirty control patients were enrolled in the present cross-sectional study. Fasting venous blood were collected and analyzed for fasting plasma glucose, hemoglobin A1c, lipid profile, and hs-CRP. The psoriasis patients were assessed for skin severity by PASI scoring. The correlation was assessed by regression analysis. Results: The hs-CRP level was found significantly higher in the psoriasis group (p-value <0.001). The hs-CRP level significantly correlated with PASI score by using multivariate regression analysis. Conclusion: This correlation between hs-CRP level and the psoriasis severity has led to the proposition that hs-CRP be used as a biomarker for overall inflammation including skin severity and cardiovascular risk factor in psoriasis.

Congenital self-healing reticulohistiocytosis presented with multiple hypopigmented flat-topped papules: a case report and review of literatures.

Congenital self-healing reticulohistiocytosis, also known as Hashimoto-Pritzker disease, is a single system Langerhans cell histiocytosis that typically presents in healthy newborns and spontaneously regresses. In the present report, we described a 2-month-old Thai female newborn with multiple hypopigmented flat-topped papules without any internal organ involvement including normal blood cell count, urinary examination, liver and renal functions, bone scan, chest X-ray, abdominal ultrasound, and bone marrow biopsy. The histopathology revealed typical findings of Langerhans cell histiocytosis, which was confirmed by the immunohistochemical staining CDla and S100. Our patient's lesions had spontaneously regressed within afew months, and no new lesion recurred afterfour months follow-up.