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• W2275454037 abstract "The epidermal protein filaggrin is essential for the structural organization and water-binding capacity of the stratum corneum. Null mutations (R501X, 2282del4, and 2447X) in FLG are common and are observed in 8–10% of the European population (Thyssen et al., 2010Thyssen J.P. Johansen J.D. Linneberg A. Menné T. Nielsen N.H. Meldgaard M. et al.The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population.Br J Dermatol. 2010; 162: 1278-1285Crossref PubMed Scopus (98) Google Scholar), and it has been shown that FLG mutations increase susceptibility to irritant contact dermatitis (ICD) (De Jongh et al., 2008De Jongh C. Khrenova L. Verberk M. Calkoen F. Van Dijk F. Voss H. et al.Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: a case-control study.Br J Dermatol. 2008; 159: 621-627Crossref PubMed Scopus (126) Google Scholar, Visser et al., 2013Visser M.J. Landeck L. Campbell L.E. McLean W.H. Weidinger S. Calkoen F. et al.Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis.Br J Dermatol. 2013; 168: 326-332Crossref PubMed Scopus (83) Google Scholar). The highest risk of developing chronic ICD on the hands is associated with FLG mutations coexisting with atopic dermatitis (AD), as seen in a consecutive clinical study on patients with chronic ICD on the hands (Visser et al., 2013Visser M.J. Landeck L. Campbell L.E. McLean W.H. Weidinger S. Calkoen F. et al.Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis.Br J Dermatol. 2013; 168: 326-332Crossref PubMed Scopus (83) Google Scholar). In stratum corneum, filaggrin degrades into its constituent amino acids and becomes a prominent part of the natural moisturizing factor (NMF) (Rawlings and Harding, 2004Rawlings A.V. Harding C.R. Moisturization and skin barrier function.Dermatol Ther. 2004; 17: 43-48Crossref PubMed Google Scholar). Thus, quantification of NMF has been used as a proxy for the amount of filaggrin and correlated with FLG mutation genotypes (Kezic et al., 2009Kezic S. Kammeyer A. Calkoen F. Fluhr J.W. Bos J.D. Natural moisturizing factor components in the stratum corneum as biomarkers of filaggrin genotype: evaluation of minimally invasive methods.Br J Dermatol. 2009; 161: 1098-1104Crossref PubMed Scopus (117) Google Scholar). Furthermore, filaggrin breakdown products are decreased among individuals with AD, with FLG genotype being the major determinant of NMF quantity (Kezic et al., 2011Kezic S. O’Regan G.M. Yau N. Sandilands A. Chen H. Campbell L.E. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy. 2011; 66: 934-940Crossref PubMed Scopus (209) Google Scholar). The total lack of filaggrin in R501X homozygous carriers is supported by immunohistochemical staining (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O’Regan G.M. Clayton T.H. Watson R.M. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet. 2007; 39: 650-654Crossref PubMed Scopus (517) Google Scholar). Whether heterozygous mutation carriers express only half the amount of filaggrin protein compared with wild-type carriers is currently unknown. In the present study, we developed a quantitative immunoassay for filaggrin in ex vivo samples, allowing the evaluation of how FLG mutations, AD, and external stimuli correlated with the epidermal content of this protein. The study was approved by the local ethical committee (H–1–2011–011), and written informed consent was obtained from all participants. Protein was extracted from the epidermal layer of 4-mm skin biopsy samples from the left upper arms of 67 individuals (Bandier et al., 2015Bandier J. Carlsen B.C. Rasmussen M.A. Petersen L.J. Johansen J.D. Skin reaction and regeneration after single SLS exposure stratified by filaggrin genotype and atopic dermatitis.Br J Dermatol. 2015; 172: 1519-1529Crossref PubMed Scopus (23) Google Scholar), stratified by AD and FLG mutations, both before and after exposure to 0.50% sodium lauryl sulfate (SLS) using an 18-mm Finn chamber. Biopsy samples were taken 1, 25, and 145 hours after removal of the Finn chamber to evaluate the immediate and prolonged effects. The distribution of AD and FLG mutations in our population throughout the trial is shown in the Supplementary Materials online (see Supplementary Table S1 online), and from this distribution, two different groupings were created: the first based solely on genotype and the second on phenotype and genotype. Filaggrin was quantified by an in-house–developed solid-phase immunoassay and expressed as the amount of filaggrin divided by the dry epidermal weight (AU/mgepi). The clinical setup, extraction, and quantification are described in the Supplementary Materials. We found a statistically significant genotype-dependent relation between the amount of epidermal filaggrin and the number of functional alleles (Mann-Whitney test, P < 0.001) (Figure 1a). When stratifying for the absence of AD, we found a decrease (49%) in filaggrin content between FLG wild type carriers (n = 20) and FLG heterozygous carriers (n = 10) (Table 1). Figure 1b clearly shows that the amount of filaggrin significantly decreased (P < 0.001) according to both FLG status and AD, although primarily driven by genotype.Table 1Distribution of filaggrin (AU/mg epidermis) according to AD and filaggrin mutation carrier statusTime After Removal of ChamberFilaggrin, AU/mg epidermis (25th–75th percentile)Controln = 20FLGwtplusADn = 19FLGhetnonADn = 10FLGhetplusADn = 10FLGhomplusADn = 8Baseline195 (108–486)150 (41–352)100 (24–172)44 (16–93)0.42 (0.29–1.70)1 hour300 (224–474)278 (188–450)120 (55–219)170 (90–228)0.65 (0.22–2.21)25 hours74 (24–105)74 (36–113.7)48 (35–128)30 (10–57)0.33 (0.23–0.72)145 hours44 (24–91)26 (11–44)22 (17–32)21 (12–31)0.17 (0.16–0.33)Abbreviation: AU, arbitrary units. Open table in a new tab Abbreviation: AU, arbitrary units. After SLS irritation, the genotype-dependent pattern of decreasing filaggrin content according to FLG mutation carrier status was still apparent (Figure 1c and d). In addition, accumulation of filaggrin protein was evident 1 hour after removal of the Finn chamber (Table 1), followed by a consistent decrease in all five groups, probably due to of SLS. Filaggrin is an important protein in the upper layers of the epidermis (Ross-Hansen et al., 2014Ross-Hansen K. Ostergaard O.O. Tanassi J.T. Thyssen J.P. Johansen J.D. Menné T. Filaggrin is a predominant member of the denaturation-resistant nickel-binding proteome of human epidermis.J Invest Dermatol. 2014; 134: 1164-1166Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Its significance in different skin conditions has previously been evaluated by genotyping (Meldgaard et al., 2012Meldgaard M. Szecsi P.B. Carlsen B.C. Thyssen J.P. Johansen J.D. Menné T. A novel multiplex analysis of filaggrin polymorphisms: a universally applicable method for genotyping.Clin Chim Acta. 2012; 413: 1488-1492Crossref PubMed Scopus (48) Google Scholar), gene expression (Torma et al., 2008Torma H. Lindberg M. Berne B. Skin barrier disruption by sodium lauryl sulfate-exposure alters the expressions of involucrin, transglutaminase 1, profilaggrin, and kallikreins during the repair phase in human skin in vivo.J Invest Dermatol. 2008; 128: 1212-1219Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), immunhistochemistry (Sybert et al., 1985Sybert V.P. Dale B.A. Holbrook K.A. Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules.J Invest Dermatol. 1985; 84: 191-194Abstract Full Text PDF PubMed Scopus (243) Google Scholar, Howell et al., 2009Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. Debenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2009; 124: R7-R12Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar), and degradation product measurements (Kezic et al., 2009Kezic S. Kammeyer A. Calkoen F. Fluhr J.W. Bos J.D. Natural moisturizing factor components in the stratum corneum as biomarkers of filaggrin genotype: evaluation of minimally invasive methods.Br J Dermatol. 2009; 161: 1098-1104Crossref PubMed Scopus (117) Google Scholar). Here, we quantify filaggrin directly and show a clear dose-response relation between filaggrin content and mutation carrier status. In FLG homozygous carriers, filaggrin was present only at the detection limits of the assay. This is in keeping with immunohistochemical findings (Sybert et al., 1985Sybert V.P. Dale B.A. Holbrook K.A. Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules.J Invest Dermatol. 1985; 84: 191-194Abstract Full Text PDF PubMed Scopus (243) Google Scholar, Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O’Regan G.M. Clayton T.H. Watson R.M. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet. 2007; 39: 650-654Crossref PubMed Scopus (517) Google Scholar). Furthermore, at baseline a 50% decrease in filaggrin content was seen in heterozygous compared with wild-type carriers without AD. When the individuals were divided into genotypes and phenotypes, AD was associated with a trend toward an additional decrease in filaggrin baseline levels. Although this was statistically nonsignificant, the finding is in accordance with NMF measurements (Angelova-Fischer et al., 2014Angelova-Fischer I. Dapic I. Hoek A.K. Jakasa I. Fischer T.W. Zillikens D. Kezic S. Skin barrier integrity and natural moisturising factor levels after cumulative dermal exposure to alkaline agents in atopic dermatitis.Acta Derm Venereol. 2014; 94: 640-644Crossref PubMed Scopus (52) Google Scholar). Upon induced skin irritation we found an initial increase of filaggrin on day 2 (1 hour after removal), which could be due to the accumulation of filaggrin (i.e., decreased degradation) rather than expression changes. Because physical occlusion augments the skin’s humidity, the processing of filaggrin into water-binding amino acids could possibly be superfluous. The increase could also reflect an accelerated release of filaggrin from hyaline granules in response to irritants. However, in a Swedish study, mRNA expression of profilaggrin in response to 1% SLS did not increase initially (Torma et al., 2008Torma H. Lindberg M. Berne B. Skin barrier disruption by sodium lauryl sulfate-exposure alters the expressions of involucrin, transglutaminase 1, profilaggrin, and kallikreins during the repair phase in human skin in vivo.J Invest Dermatol. 2008; 128: 1212-1219Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar) but showed a compensatory increase in the repair phase after barrier disruption 4–7 days later. In the present study we found a decrease in filaggrin that was not followed by an increase. Furthermore, our results may indicate an even higher degradation rate of filaggrin protein attributable to the SLS-induced xerosis inducing release of the amino acids to counteract the barrier disruption. In groups with the same mutation status but with different phenotypes (FLG hetnonAD and FLG hetplusAD), individuals with AD had slightly less filaggrin than individuals without AD. This decrease of filaggrin in response to SLS could indicate a functional filaggrin deficiency, but it could also be explained by an increased utilization of amino acids to compensate for the xerosis among individuals with AD. The present study is, to our knowledge, the first to determine the quantity of filaggrin in human epidermis at the protein level before and after barrier disruption. Additionally, we could quantitatively assess the effects of both AD status and FLG mutation carrier status. In summary, we have established a method to quantify the protein levels of filaggrin in ex vivo skin samples. We have shown significant reduction in the filaggrin content in direct proportion to the number of functional FLG alleles, and we suggest that AD may further affect filaggrin protein content. We have shown that after irritation with SLS under occlusion, the filaggrin content increases initially but then continuously decreases long after terminating irritant exposure. The authors state no conflict of interests. We would like to thank the Department of Clinical Biochemistry at Gentofte Hospital for the genotyping of the participants. For the financial support we thank the Aage Bangs foundation and the Copenhagen County Research Foundation. Download .pdf (.18 MB) Help with pdf files Supplementary Materials" @default.
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• W2275454037 date "2016-06-01" @default.
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• W2275454037 title "Quantification of Epidermal Filaggrin in Human Skin and its Response to Skin Irritation" @default.
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