Steroid concentrations in atopic dermatitis patients: Reduced plasma DHEAS and increased cortisone levels.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease, which is characterized by a disrupted epidermal barrier function present both in affected skin and in non-affected skin. Mainly glucocorticosteroids were used in topical and systemic atopy treatments because of their potent anti-inflammatory effects, unfortunately with strong side effects. In this study we determined that 2 out of 16 steroids were significantly different in healthy volunteers vs AD-patients. Cortisone, which is higher in AD-patients plasma, is a direct precursor of the bioactive corticosteroid cortisol, which just displays a higher tendency and is known for its potent anti-inflammatory effects. In addition a tendency of reduced levels of the anti-inflammatory ER ligand estrone was found in AD-patients. DHEA is a precursor of testosterone, its levels just display a lower tendency in male AD-patients, while its sulfonation metabolite DHEAS is lower in male and female AD-patients. We found and conclude that altered steroid levels in the plasma of AD-patients indicate altered vitamin D signaling (based on reduced DHEA sulfonation) and increased feedback for anti-inflammatory signaling (increased levels of cortisone) present in AD-patients. This article is protected by copyright. All rights reserved

Reduced Carotenoid and Retinoid Concentrations and Altered Lycopene Isomer Ratio in Plasma of Atopic Dermatitis Patients.

Carotenoids and retinoids are known to alter the allergic response with important physiological roles in the skin and the immune system. In the human organism various carotenoids are present, some of which are retinoid precursors. The bioactive derivatives of these retinoids are the retinoic acids, which can potently activate nuclear hormone receptors such as the retinoic acid receptor and the retinoid X receptor. In this study, we aimed to assess how plasma carotenoid and retinoid concentrations along with the ratio of their isomers are altered in atopic dermatitis (AD) patients (n = 20) compared to healthy volunteers (HV, n = 20). The study indicated that plasma levels of the carotenoids lutein (HV 198 ± 14 ng/mL, AD 158 ± 12 ng/mL, p = 0.02; all values in mean ± SEM), zeaxanthin (HV 349 ± 30 ng/mL, AD 236 ± 18 ng/mL, p ≤ 0.01), as well as the retinoids retinol (HV 216 ± 20 ng/mL, AD 167 ± 17 ng/mL, p = 0.04) and all-trans-retinoic acid (HV 1.1 ± 0.1 ng/mL, AD 0.7 ± 0.1 ng/mL, p = 0.04) were significantly lower in the AD-patients, while lycopene isomers, α-carotene, and β-carotene levels were comparable to that determined in the healthy volunteers. In addition, the ratios of 13-cis- vs. all-trans-lycopene (HV 0.31 ± 0.01, AD 0.45 ± 0.07, p = 0.03) as well as 13-cis- vs. all-trans-retinoic acid (HV 1.4 ± 0.2, AD 2.6 ± 0.6, p = 0.03) were increased in the plasma of AD-patients indicating an AD-specific 13-cis-isomerisation. A positive correlation with SCORAD was calculated with 13-cis- vs. all-trans-lycopene ratio (r = 0.40, p = 0.01), while a negative correlation was observed with zeaxanthin plasma levels (r = -0.42, p = 0.01). Based on our results, we conclude that in the plasma of AD-patients various carotenoids and retinoids are present at lower concentrations, while the ratio of selected lycopene isomers also differed in the AD-patient group. An increase in plasma isomers of both lycopene and retinoic acid may cause an altered activation of nuclear hormone receptor signaling pathways and thus may be partly responsible for the AD-phenotype

Identification of factor XIII-A as a marker of alternative macrophage activation

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Detection of factor XIII-A is a valuable tool for distinguishing dendritic cells and tissue macrophages in granuloma annulare and necrobiosis lipoidica.

BACKGROUND Factor XIII subunit A (FXIII-A) is used as a diagnostic marker in a wide range of dermatological diseases ranging from inflammatory lesions to malignancies, although neither the cell types responsible for its expression nor the mechanism(s) resulting in its local accumulation in pathological conditions have been characterized. OBJECTIVE In this study, we aimed to gain information on the cells showing an immunohistochemical reaction for FXIII-A and answer the question whether macrophages and/or dendritic cells are labelled for FXIII-A. METHODS We carried out our studies on samples of granuloma annulare (GA) and necrobiosis lipoidica (NL), the prime examples for granulomatous skin lesions with a non-infectious background in which extracellular matrix remodelling is a key feature without any sign of malignant transformation. We used markers for macrophages and dendritic cells in combination with the detection of FXIII-A in double labelling immunohistochemical reactions. RESULTS We demonstrated that FXIII-A positivity clearly distinguishes macrophages (CD163+/FXIII-A+) from dendritic cells (CD11c+/FXIII-A-) not only in the normal dermis as previously described by Zaba et al. (J Clin Invest 2007; 117: 2517-2525) but also in the pathological conditions of GA and NL. Detecting the expression of DC-SIGN/CD209 and mannose receptor molecules on FXIII-A+ macrophages we confirmed that FXIII-A is expressed in the alternatively activated macrophages. However, while DC-SIGN/CD209 was invariably expressed on FXIII-A+ cells both in normal and pathological conditions of GA/NL (98.7% vs. 93.5/96%), mannose receptor was only partially coexpressed with FXIII-A (94.8% vs. 74.7/52.2%), suggesting that FXIII-A+ macrophages do not represent a homogenous population. CONCLUSIONS FXIII-A selectively marks macrophages and distinguishes them from dendritic cells. The presence of FXIII-A is not a disease-specific marker but indicates a possible common mechanism of macrophage activation in various dermatological diseases

Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation

In pathological conditions, F0F1-ATPase hydrolyzes ATP in an attempt to maintain mitochondrial membrane potential. Using thermodynamic assumptions and computer modeling, we established that mitochondrial membrane potential can be more negative than the reversal potential of the adenine nucleotide translocase (ANT) but more positive than that of the F0F1-ATPase. Experiments on isolated mitochondria demonstrated that, when the electron transport chain is compromised, the F0F1-ATPase reverses, and the membrane potential is maintained as long as matrix substrate-level phosphorylation is functional, without a concomitant reversal of the ANT. Consistently, no cytosolic ATP consumption was observed using plasmalemmal KATP channels as cytosolic ATP biosensors in cultured neurons, in which their in situ mitochondria were compromised by respiratory chain inhibitors. This finding was further corroborated by quantitative measurements of mitochondrial membrane potential, oxygen consumption, and extracellular acidification rates, indicating nonreversal of ANT of compromised in situ neuronal and astrocytic mitochondria; and by bioluminescence ATP measurements in COS-7 cells transfected with cytosolic- or nuclear-targeted luciferases and treated with mitochondrial respiratory chain inhibitors in the presence of glycolytic plus mitochondrial vs. only mitochondrial substrates. Our findings imply the possibility of a rescue mechanism that is protecting against cytosolic/nuclear ATP depletion under pathological conditions involving impaired respiration. This mechanism comes into play when mitochondria respire on substrates that support matrix substrate-level phosphorylation.—Chinopoulos, C., Gerencser, A. A., Mandi, M., Mathe, K., Töröcsik, B., Doczi, J., Turiak, L., Kiss, G., Konràd, C., Vajda, S., Vereczki, V., Oh, R. J., Adam-Vizi, V. Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation