41 results on '"Gutowska-Owsiak D"'
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2. Histamine enhances keratinocyte-mediated resolution of inflammation by promoting wound healing and response to infection
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Gutowska-Owsiak, D., Selvakumar, T. A., Salimi, M., Taylor, S., and Ogg, G. S.
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- 2014
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3. Cytokine regulation of the epidermal barrier
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Gutowska-Owsiak, D. and Ogg, G. S.
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- 2013
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4. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes
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Gutowska-Owsiak, D., Schaupp, A. L., Salimi, M., Taylor, S., and Ogg, G. S.
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- 2011
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5. Interleukin-22-mediated downregulation of filaggrin expression in keratinocytes is an important mechanism in pathogenesis of atopic dermatitis: 166
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Gutowska-Owsiak, D and Ogg, G
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- 2010
6. Expression of histamine-synthesizing enzyme, histidine decarboxylase, by keratinocytes and its regulation by cytokines and factors relevant to atopic skin disease
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Gutowska-Owsiak, D, Greenwald, L, Watson, C, Selvakumar, TA, and Ogg, GS
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- 2016
7. The role of type 2 innate lymphoid cells in the pathogenesis of atopic dermatitis
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Salimi, M, Barlow, J, Saunders, S, Xue, L, Gutowska-Owsiak, D, Wang, X, Huang, L-C, Johnson, D, Scanlon, S, McKenzie, A, Fallon, P, and Ogg, G
- Published
- 2016
8. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion
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Gutowska-Owsiak, D, Schaupp, AL, Salimi, M, Selvakumar, TA, McPherson, T, Taylor, S, and Ogg, GS
- Subjects
integumentary system - Abstract
Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target.
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- 2016
9. Deficiency of filaggrin regulates endogenous cysteine protease activity, leading to impaired skin barrier function
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Wang, X. W., primary, Wang, J. J., additional, Gutowska-Owsiak, D., additional, Salimi, M., additional, Selvakumar, T. A., additional, Gwela, A., additional, Chen, L. Y., additional, Wang, Y. J., additional, Giannoulatou, E., additional, and Ogg, G., additional
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- 2017
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10. Histamine exerts multiple effects on expression of genes associated with epidermal barrier function
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Gutowska-Owsiak, D., Salimi, M., Selvakumar, T. A., Wang, X., Taylor, S., and Graham Ogg
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Keratinocytes ,Cysteine Endopeptidases ,Intermediate Filament Proteins ,integumentary system ,Humans ,Filaggrin Proteins ,Cells, Cultured ,Histamine - Abstract
BACKGROUND: The role of epidermal barrier genes in the pathogenesis of atopic skin inflammation has recently been highlighted. Cytokines that are abundant in the skin during inflammation have been shown to exert various effects on the expression of barrier genes, although the role of histamine in this area of skin biology is not yet fully understood. OBJECTIVE: To assess the effect of stimulation with histamine on keratinocytes by analysis of the pathways involved in epidermal barrier integrity. MATERIAL AND METHODS: We performed a gene expression analysis of histamine-stimulated keratinocytes. Functional changes were tested using the dye penetration assay. Differential changes in filaggrin and the filaggrin-processing enzyme bleomycin hydrolase (BLMH) were validated at the protein level, and expression was also assessed in filaggrin knock-down keratinocytes. RESULTS: Histamine altered expression of multiple barrier genes. Expression of filaggrin was downregulated, as was that of other markers, thus suggesting the presence of delayed/aberrant keratinocyte differentiation. Expression of genes involved in cellular adhesiveness and genes of protease expression was dysregulated, but expression of protease inhibitors was increased. BLMH was upregulated in keratinocytes subjected to histamine and filaggrin knockdown. CONCLUSIONS: Histamine exerts a dual effect on epidermal barrier genes; it suppresses keratinocyte differentiation and dysregulates genes of cellular adhesiveness, although it induces genes contributing to stratum corneum function. Upregulation of BLMH and protease inhibitors could support maintenance of the permeability barrier by enhanced generation of moisturizing compounds and suppressed desquamation. In contrast, in the case of stratum corneum damage, histamine could enhance transcutaneous sensitization.
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- 2014
11. Interleukin-17 mediates adhesion impairment in human keratinocytes - potential involvement in barrier dysfunction during atopic skin inflammation
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Gutowska-Owsiak, D, Schaupp, A, Taylor, S, and Ogg, G
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- 2012
12. Interleukin-17 and interleukin-22 contribute to alterations in epidermal function via multiple pathways - role in atopic eczema
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Gutowska-Owsiak, D, Schaupp, A, Salimi, M, Chiang, C, Taylor, S, and Ogg, G
- Published
- 2011
13. IL-17 influences expression of genes associated with barrier function in keratinocytes
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Gutowska-Owsiak, D, Chan, H, Schaupp, A, Taylor, S, and Ogg, G
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- 2011
14. IL-17A and IL-22 cause down-regulation of filaggrin - implications for the pathogenesis of atopic eczema
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Gutowska-Owsiak, D, Schaupp, A, Taylor, S, and Ogg, G
- Published
- 2010
15. 2‐Dimensional gel electrophoresis and MALDI‐MS of cystic cervical metastasis from head and neck squamous cell carcinoma
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Beer, H.L., primary, Jenkins, R.E., additional, Gutowska‐Owsiak, D., additional, Pazmany, L., additional, Birchall, M.A., additional, and Kitteringham, N.R., additional
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- 2006
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16. The mucosal immune response to laryngopharyngeal reflux.
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Rees LE, Pazmany L, Gutowska-Owsiak D, Inman CF, Phillips A, Stokes CR, Johnston N, Koufman JA, Postma G, Bailey M, Birchall MA, Rees, Louisa E N, Pazmany, Laszlo, Gutowska-Owsiak, Danuta, Inman, Charlotte F, Phillips, Anne, Stokes, Christopher R, Johnston, Nikki, Koufman, Jamie A, and Postma, Gregory
- Abstract
Rationale: Laryngopharyngeal reflux (LPR) affects up to 20% of Western populations. Although individual morbidity is usually moderate, treatment costs are high and there are associations with other diseases, including laryngeal cancer. To date, there have been no studies of the mucosal immune response to this common inflammatory disease.Objectives: To determine the mucosal immune response to LPR.Methods: We performed a prospective immunologic study of laryngeal biopsies from patients with LPR and control subjects (n = 12 and 11, respectively), and of primary laryngeal epithelial cells in vitro.Measurements and Main Results: Quantitative multiple-color immunofluorescence, using antibodies for lymphocytes (CD4, CD8, CD3, CD79, CD161), granulocytes (CD68, EMBP), monocytic cells (CD68, major histocompatibility complex [MHC] class II), and classical and nonclassical MHC (I, II, beta(2)-microglobulin, CD1d). Univariate and multivariate analysis and colocalization measurements were applied. There was an increase in percentage area of mucosal CD8(+) cells in the epithelium (P < 0.005), whereas other leukocyte and granulocyte antigens were unchanged. Although epithelial MHC class I and II expression was unchanged by reflux, expression of the nonclassical MHC molecule CD1d increased (P < 0.05, luminal layers). In vitro, laryngeal epithelial cells constitutively expressed CD1d. CD1d and MHC I expression were inversely related in all subjects, in a pattern which appears to be unique to the upper airway. Colocalization of natural killer T (NKT) cells with CD1d increased in patients (P < 0.01).Conclusions: These data indicate a role for the CD1d-NKT cell axis in response to LPR in humans. This represents a useful target for novel diagnostics and treatments in this common condition. [ABSTRACT FROM AUTHOR]- Published
- 2008
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17. Keratinocyte-derived small extracellular vesicles supply antigens for CD1a-resticted T cells and promote their type 2 bias in the context of filaggrin insufficiency.
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Kobiela A, Hewelt-Belka W, Frąckowiak JE, Kordulewska N, Hovhannisyan L, Bogucka A, Etherington R, Piróg A, Dapic I, Gabrielsson S, Brown SJ, Ogg GS, and Gutowska-Owsiak D
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- Humans, Filaggrin Proteins, Inflammation, Intermediate Filament Proteins genetics, Keratinocytes, Lipids, Peptides metabolism, Proteomics, T-Lymphocytes metabolism, Dermatitis, Atopic, Extracellular Vesicles metabolism
- Abstract
Introduction: Exosome-enriched small extracellular vesicles (sEVs) are nanosized organelles known to participate in long distance communication between cells, including in the skin. Atopic dermatitis (AD) is a chronic inflammatory skin disease for which filaggrin ( FLG ) gene mutations are the strongest genetic risk factor. Filaggrin insufficiency affects multiple cellular function, but it is unclear if sEV-mediated cellular communication originating from the affected keratinocytes is also altered, and if this influences peptide and lipid antigen presentation to T cells in the skin., Methods: Available mRNA and protein expression datasets from filaggrin-insufficient keratinocytes (shFLG), organotypic models and AD skin were used for gene ontology analysis with FunRich tool. sEVs secreted by shFLG and control shC cells were isolated from conditioned media by differential centrifugation. Mass spectrometry was carried out for lipidomic and proteomic profiling of the cells and sEVs. T cell responses to protein, peptide, CD1a lipid antigens, as well as phospholipase A2-digested or intact sEVs were measured by ELISpot and ELISA., Results: Data analysis revealed extensive remodeling of the sEV compartment in filaggrin insufficient keratinocytes, 3D models and the AD skin. Lipidomic profiles of shFLGsEV showed a reduction in the long chain (LCFAs) and polyunsaturated fatty acids (PUFAs; permissive CD1a ligands) and increased content of the bulky headgroup sphingolipids (non-permissive ligands). This resulted in a reduction of CD1a-mediated interferon-γ T cell responses to the lipids liberated from shFLG-generated sEVs in comparison to those induced by sEVs from control cells, and an increase in interleukin 13 secretion. The altered sEV lipidome reflected a generalized alteration in the cellular lipidome in filaggrin-insufficient cells and the skin of AD patients, resulting from a downregulation of key enzymes implicated in fatty acid elongation and desaturation, i.e., enzymes of the ACSL, ELOVL and FADS family., Discussion: We determined that sEVs constitute a source of antigens suitable for CD1a-mediated presentation to T cells. Lipids enclosed within the sEVs secreted on the background of filaggrin insufficiency contribute to allergic inflammation by reducing type 1 responses and inducing a type 2 bias from CD1a-restricted T cells, thus likely perpetuating allergic inflammation in the skin., Competing Interests: Author GO has served on advisory boards or holds consultancies or research grants with Eli Lilly, Novartis, Janssen, BMS and UCB Pharma, Regeneron/Sanofi, Roche, Anaptysbio. GO has patent filed in the CD1a field. SJB holds or has recently held research grants from the Wellcome Trust, British Skin Foundation, EU/IMI H2020 ‘BIOMAP’, European Lead Factory, Charles Wolfson Charitable Trust, Rosetrees Trust, Stoneygate Trust, Pfizer, and consultancies with Abbvie, Sosei Heptares and Janssen. SG has a patent on B-cell targeting of EVs and is scientific advisor of Anjarium Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kobiela, Hewelt-Belka, Frąckowiak, Kordulewska, Hovhannisyan, Bogucka, Etherington, Piróg, Dapic, Gabrielsson, Brown, Ogg and Gutowska-Owsiak.)
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- 2024
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18. Editorial: Novel aspects of the immunological and structural barrier of the epidermis.
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O'Shaughnessy R, Common J, and Gutowska-Owsiak D
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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19. Genome-Wide DNA Methylation and Gene Expression in Patients with Indolent Systemic Mastocytosis.
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Górska A, Urbanowicz M, Grochowalski Ł, Seweryn M, Sobalska-Kwapis M, Wojdacz T, Lange M, Gruchała-Niedoszytko M, Jarczak J, Strapagiel D, Górska-Ponikowska M, Pelikant-Małecka I, Kalinowski L, Nedoszytko B, Gutowska-Owsiak D, and Niedoszytko M
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- Adult, Humans, DNA Methylation, Epigenesis, Genetic, Tryptases genetics, Oncogenes, DNA, Gene Expression, CpG Islands, Forkhead Transcription Factors genetics, Mastocytosis, Systemic genetics, Mastocytosis, Systemic diagnosis, Anaphylaxis genetics
- Abstract
Mastocytosis is a clinically heterogenous, usually acquired disease of the mast cells with a survival time that depends on the time of onset. It ranges from skin-limited to systemic disease, including indolent and more aggressive variants. The presence of the oncogenic KIT p. D816V gene somatic mutation is a crucial element in the pathogenesis. However, further epigenetic regulation may also affect the expression of genes that are relevant to the pathology. Epigenetic alterations are responsible for regulating the expression of genes that do not modify the DNA sequence. In general, it is accepted that DNA methylation inhibits the binding of transcription factors, thereby down-regulating gene expression. However, so far, little is known about the epigenetic factors leading to the clinical onset of mastocytosis. Therefore, it is essential to identify possible epigenetic predictors, indicators of disease progression, and their link to the clinical picture to establish appropriate management and a therapeutic strategy. The aim of this study was to analyze genome-wide methylation profiles to identify differentially methylated regions (DMRs) in patients with mastocytosis compared to healthy individuals, as well as the genes located in those regulatory regions. Genome-wide DNA methylation profiling was performed in peripheral blood collected from 80 adult patients with indolent systemic mastocytosis (ISM), the most prevalent subvariant of mastocytosis, and 40 healthy adult volunteers. A total of 117 DNA samples met the criteria for the bisulfide conversion step and microarray analysis. Genome-wide DNA methylation analysis was performed using a MethylationEPIC BeadChip kit. Further analysis was focused on the genomic regions rather than individual CpG sites. Co-methylated regions (CMRs) were assigned via the CoMeBack method. To identify DMRs between the groups, a linear regression model with age as the covariate on CMRs was performed using Limma. Using the available data for cases only, an association analysis was performed between methylation status and tryptase levels, as well as the context of allergy, and anaphylaxis. KEGG pathway mapping was used to identify genes differentially expressed in anaphylaxis. Based on the DNA methylation results, the expression of 18 genes was then analyzed via real-time PCR in 20 patients with mastocytosis and 20 healthy adults. A comparison of the genome-wide DNA methylation profile between the mastocytosis patients and healthy controls revealed significant differences in the methylation levels of 85 selected CMRs. Among those, the most intriguing CMRs are 31 genes located within the regulatory regions. In addition, among the 10 CMRs located in the promoter regions, 4 and 6 regions were found to be either hypo- or hypermethylated, respectively. Importantly, three oncogenes- FOXQ1 , TWIST1 , and ERG -were identified as differentially methylated in mastocytosis patients, for the first time. Functional annotation revealed the most important biological processes in which the differentially methylated genes were involved as transcription, multicellular development, and signal transduction. The biological process related to histone H2A monoubiquitination (GO:0035518) was found to be enriched in association with higher tryptase levels, which may be associated with more aberrant mast cells and, therefore, more atypical mast cell disease. The signal in the BAIAP2 gene was detected in the context of anaphylaxis, but no significant differential methylation was found in the context of allergy. Furthermore, increased expression of genes encoding integral membrane components ( GRM2 and KRTCAP3 ) was found in mastocytosis patients. This study confirms that patients with mastocytosis differ significantly in terms of methylation levels in selected CMRs of genes involved in specific molecular processes. The results of gene expression profiling indicate the increased expression of genes belonging to the integral component of the membrane in mastocytosis patients ( GRM2 and KRTCAP3 ). Further work is warranted, especially in relation to the disease subvariants, to identify links between the methylation status and the symptoms and novel therapeutic targets.
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- 2023
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20. Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2-dependent fashion.
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Kobiela A, Hovhannisyan L, Jurkowska P, de la Serna JB, Bogucka A, Deptuła M, Paul AA, Panek K, Czechowska E, Rychłowski M, Królicka A, Zieliński J, Gabrielsson S, Pikuła M, Trzeciak M, Ogg GS, and Gutowska-Owsiak D
- Subjects
- Humans, Staphylococcus aureus, Toll-Like Receptor 2 metabolism, Filaggrin Proteins, Mortality, Premature, Keratinocytes metabolism, Extracellular Vesicles metabolism, Staphylococcal Infections
- Abstract
Filaggrin (FLG) protein is indispensable for multiple aspects of the epidermal barrier function but its accumulation in a monomeric filaggrin form may initiate premature keratinocytes death; it is unclear how filaggrin levels are controlled before the formation of storing keratohyalin granules. Here we show that keratinocyte-secreted small extracellular vesicles (sEVs) may contain filaggrin-related cargo providing a route of eliminating excess filaggrin from keratinocytes; blocking of sEV release has cytotoxic effects on those cells. Filaggrin-containing sEVs are found in plasma in both healthy individuals and atopic dermatitis patients. Staphylococcus aureus (S. aureus) enhances packaging and secretion of filaggrin-relevant products within the sEVs for enhanced export via a TLR2-mediated mechanism which is also linked to the ubiquitination process. This filaggrin removal system, preventing premature keratinocyte death and epidermal barrier dysfunction, is exploited by S. aureus which promotes filaggrin elimination from the skin that could help safeguard bacterial growth., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)
- Published
- 2023
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21. In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers.
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Paul AA, Szulc NA, Kobiela A, Brown SJ, Pokrzywa W, and Gutowska-Owsiak D
- Abstract
Background: Loss of function mutation in FLG is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by FLG . Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin. Objective: To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover. Methods: The effect of inhibition of proteasome and deubiquitinases on the level and modifications of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed in silico using the DEGRONOPEDIA and Clustal Omega tool. Results: Inhibition of proteasome and deubiquitinases stabilizes profilaggrin and its high molecular weight of presumably ubiquitinated derivatives. In silico analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. FLG mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes. Conclusion: The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. FLG mutations alter those key elements, affecting the degradation routes and the mutated products' stability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Paul, Szulc, Kobiela, Brown, Pokrzywa and Gutowska-Owsiak.)
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- 2023
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22. Corrigendum: Ni 2+ -assisted hydrolysis may affect the human proteome; filaggrin degradation ex vivo as an example of possible consequences.
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Podobas EI, Gutowska-Owsiak D, Moretti S, Poznański J, Kulińczak M, Grynberg M, Gruca A, Bonna A, Płonka D, Frączyk T, Ogg G, and Bal W
- Abstract
[This corrects the article DOI: 10.3389/fmolb.2022.828674.]., (Copyright © 2022 Podobas, Gutowska-Owsiak, Moretti, Poznański, Kulińczak, Grynberg, Gruca, Bonna, Płonka, Frączyk, Ogg and Bal.)
- Published
- 2022
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23. Exposure of Keratinocytes to Candida Albicans in the Context of Atopic Milieu Induces Changes in the Surface Glycosylation Pattern of Small Extracellular Vesicles to Enhance Their Propensity to Interact With Inhibitory Siglec Receptors.
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Kobiela A, Frackowiak JE, Biernacka A, Hovhannisyan L, Bogucka AE, Panek K, Paul AA, Lukomska J, Wang X, Giannoulatou E, Krolicka A, Zielinski J, Deptula M, Pikula M, Gabrielsson S, Ogg GS, and Gutowska-Owsiak D
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- Candida albicans, Glycosylation, Humans, Keratinocytes, Sialic Acid Binding Immunoglobulin-like Lectins, Candidiasis, Dermatitis, Atopic, Extracellular Vesicles
- Abstract
Candida albicans (C. albicans) infection is a potential complication in the individuals with atopic dermatitis (AD) and can affect clinical course of the disease. Here, using primary keratinocytes we determined that atopic milieu promotes changes in the interaction of small extracellular vesicles (sEVs) with dendritic cells and that this is further enhanced by the presence of C. albicans . sEV uptake is largely dependent on the expression of glycans on their surface; modelling of the protein interactions indicated that recognition of this pathogen through C. albicans -relevant pattern recognition receptors (PRRs) is linked to several glycosylation enzymes which may in turn affect the expression of sEV glycans. Here, significant changes in the surface glycosylation pattern, as determined by lectin array, could be observed in sEVs upon a combined exposure of keratinocytes to AD cytokines and C. albicans . This included enhanced expression of multiple types of glycans, for which several dendritic cell receptors could be proposed as binding partners. Blocking experiments showed predominant involvement of the inhibitory Siglec-7 and -9 receptors in the sEV-cell interaction and the engagement of sialic acid-containing carbohydrate moieties on the surface of sEVs. This pointed on ST6 β-Galactoside α-2,6-Sialyltransferase 1 (ST6GAL1) and Core 1 β,3-Galactosyltransferase 1 (C1GALT1) as potential enzymes involved in the process of remodelling of the sEV surface glycans upon C. albicans exposure. Our results suggest that, in combination with atopic dermatitis milieu , C. albicans promotes alterations in the glycosylation pattern of keratinocyte-derived sEVs to interact with inhibitory Siglecs on antigen presenting cells. Hence, a strategy aiming at this pathway to enhance antifungal responses and restrict pathogen spread could offer novel therapeutic options for skin candidiasis in AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kobiela, Frackowiak, Biernacka, Hovhannisyan, Bogucka, Panek, Paul, Lukomska, Wang, Giannoulatou, Krolicka, Zielinski, Deptula, Pikula, Gabrielsson, Ogg and Gutowska-Owsiak.)
- Published
- 2022
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24. Ni 2+ -Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences.
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Podobas EI, Gutowska-Owsiak D, Moretti S, Poznański J, Kulińczak M, Grynberg M, Gruca A, Bonna A, Płonka D, Frączyk T, Ogg G, and Bal W
- Abstract
Deficiency in a principal epidermal barrier protein, filaggrin (FLG), is associated with multiple allergic manifestations, including atopic dermatitis and contact allergy to nickel. Toxicity caused by dermal and respiratory exposures of the general population to nickel-containing objects and particles is a deleterious side effect of modern technologies. Its molecular mechanism may include the peptide bond hydrolysis in X
1 -S/T-c/p-H-c-X2 motifs by released Ni2+ ions. The goal of the study was to analyse the distribution of such cleavable motifs in the human proteome and examine FLG vulnerability of nickel hydrolysis. We performed a general bioinformatic study followed by biochemical and biological analysis of a single case, the FLG protein. FLG model peptides, the recombinant monomer domain human keratinocytes in vitro and human epidermis ex vivo were used. We also investigated if the products of filaggrin Ni2+ -hydrolysis affect the activation profile of Langerhans cells. We found X1 -S/T-c/p-H-c-X2 motifs in 40% of human proteins, with the highest abundance in those involved in the epidermal barrier function, including FLG. We confirmed the hydrolytic vulnerability and pH-dependent Ni2+ -assisted cleavage of FLG-derived peptides and FLG monomer, using in vitro cell culture and ex-vivo epidermal sheets; the hydrolysis contributed to the pronounced reduction in FLG in all of the models studied. We also postulated that Ni-hydrolysis might dysregulate important immune responses. Ni2+ -assisted cleavage of barrier proteins, including FLG, may contribute to clinical disease associated with nickel exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Podobas, Gutowska-Owsiak, Moretti, Poznański, Kulińczak, Grynberg, Gruca, Bonna, Płonka, Ogg and Bal.)- Published
- 2022
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25. The Role of Non-Immune Cell-Derived Extracellular Vesicles in Allergy.
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Hovhannisyan L, Czechowska E, and Gutowska-Owsiak D
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- Animals, Humans, Extracellular Vesicles immunology, Hypersensitivity immunology
- Abstract
Extracellular vesicles (EVs), and especially exosomes, have been shown to mediate information exchange between distant cells; this process directly affects the biological characteristics and functionality of the recipient cell. As such, EVs significantly contribute to the shaping of immune responses in both physiology and disease states. While vesicles secreted by immune cells are often implicated in the allergic process, growing evidence indicates that EVs from non-immune cells, produced in the stroma or epithelia of the organs directly affected by inflammation may also play a significant role. In this review, we provide an overview of the mechanisms of allergy to which those EVs contribute, with a particular focus on small EVs (sEVs). Finally, we also give a clinical perspective regarding the utilization of the EV-mediated communication route for the benefit of allergic patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hovhannisyan, Czechowska and Gutowska-Owsiak.)
- Published
- 2021
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26. Addressing Differentiation in Live Human Keratinocytes by Assessment of Membrane Packing Order.
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Gutowska-Owsiak D, Podobas EI, Eggeling C, Ogg GS, and Bernardino de la Serna J
- Abstract
Differentiation of keratinocytes is critical for epidermal stratification and formation of a protective stratum corneum . It involves a series of complex processes leading through gradual changes in characteristics and functions of keratinocytes up to their programmed cell death via cornification. The stratum corneum is a relatively impermeable barrier, comprised of dead cell remnants (corneocytes) embedded in lipid matrix. Corneocyte membranes are comprised of specialized lipids linked to late differentiation proteins, contributing to the formation of a stiff and mechanically strengthened layer. To date, the assessment of the progression of keratinocyte differentiation is only possible through determination of specific differentiation markers, e.g., by using proteomics-based approaches. Unfortunately, this requires fixation or cell lysis, and currently there is no robust methodology available to study keratinocyte differentiation in living cells in real-time. Here, we explore new live-cell based approaches for screening differentiation advancement in keratinocytes, in a "calcium switch" model. We employ a polarity-sensitive dye, Laurdan, and Laurdan general polarization function (GP) as a reporter of the degree of membrane lateral packing order or condensation, as an adequate marker of differentiation. We show that the assay is straightforward and can be conducted either on a single cell level using confocal spectral imaging or on the ensemble level using a fluorescence plate reader. Such systematic quantification may become useful for understanding mechanisms of keratinocyte differentiation, such as the role of membrane in homogeneities in stiffness, and for future therapeutic development., (Copyright © 2020 Gutowska-Owsiak, Podobas, Eggeling, Ogg and Bernardino de la Serna.)
- Published
- 2020
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27. Genetic and Epigenetic Aspects of Atopic Dermatitis.
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Nedoszytko B, Reszka E, Gutowska-Owsiak D, Trzeciak M, Lange M, Jarczak J, Niedoszytko M, Jablonska E, Romantowski J, Strapagiel D, Skokowski J, Siekierzycka A, Nowicki RJ, Dobrucki IT, Zaryczańska A, and Kalinowski L
- Subjects
- DNA Methylation genetics, Epidermis metabolism, Epigenesis, Genetic genetics, Epigenomics methods, Filaggrin Proteins, Genetic Predisposition to Disease genetics, Humans, Immunity, Innate genetics, Mutation genetics, Serine Peptidase Inhibitors, Kazal Type genetics, Skin metabolism, Skin pathology, Skin Physiological Phenomena genetics, Dermatitis, Atopic genetics, Dermatitis, Atopic metabolism
- Abstract
Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.
- Published
- 2020
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28. Re-evaluation of human BDCA-2+ DC during acute sterile skin inflammation.
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Chen YL, Gomes T, Hardman CS, Vieira Braga FA, Gutowska-Owsiak D, Salimi M, Gray N, Duncan DA, Reynolds G, Johnson D, Salio M, Cerundolo V, Barlow JL, McKenzie ANJ, Teichmann SA, Haniffa M, and Ogg G
- Subjects
- Antigen Presentation physiology, Antigens, CD1 metabolism, Humans, Interleukin-3 Receptor alpha Subunit metabolism, Lymph Nodes metabolism, Dendritic Cells metabolism, Inflammation metabolism, Lectins, C-Type metabolism, Membrane Glycoproteins metabolism, Receptors, Immunologic metabolism, Skin metabolism
- Abstract
Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN-I) and are traditionally defined as being BDCA-2+CD123+. pDCs are not readily detectable in healthy human skin, but have been suggested to accumulate in wounds. Here, we describe a CD1a-bearing BDCA-2+CD123int DC subset that rapidly infiltrates human skin wounds and comprises a major DC population. Using single-cell RNA sequencing, we show that these cells are largely activated DCs acquiring features compatible with lymph node homing and antigen presentation, but unexpectedly express both BDCA-2 and CD123, potentially mimicking pDCs. Furthermore, a third BDCA-2-expressing population, Axl+Siglec-6+ DCs (ASDC), was also found to infiltrate human skin during wounding. These data demonstrate early skin infiltration of a previously unrecognized CD123intBDCA-2+CD1a+ DC subset during acute sterile inflammation, and prompt a re-evaluation of previously ascribed pDC involvement in skin disease., (© 2019 Chen et al.)
- Published
- 2020
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29. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis.
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Chen YL, Gutowska-Owsiak D, Hardman CS, Westmoreland M, MacKenzie T, Cifuentes L, Waithe D, Lloyd-Lavery A, Marquette A, Londei M, and Ogg G
- Subjects
- Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Cell Movement drug effects, Dermatitis, Atopic immunology, Eczema immunology, Eczema metabolism, Extracellular Fluid, Humans, Inflammation drug therapy, Inflammation immunology, Inflammation metabolism, Interleukin-12 metabolism, Interleukin-33 immunology, Neutrophils drug effects, Neutrophils metabolism, Receptors, Interleukin-8A metabolism, Skin drug effects, Skin immunology, Skin metabolism, Dermatitis, Atopic drug therapy, Dermatitis, Atopic metabolism, Interleukin-33 metabolism
- Abstract
Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti-IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8-induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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30. Orchestrated control of filaggrin-actin scaffolds underpins cornification.
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Gutowska-Owsiak D, de La Serna JB, Fritzsche M, Naeem A, Podobas EI, Leeming M, Colin-York H, O'Shaughnessy R, Eggeling C, and Ogg GS
- Subjects
- Actins chemistry, Animals, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Calcium pharmacology, Cell Differentiation drug effects, Cytochalasin D pharmacology, Cytoplasmic Granules metabolism, Epidermis pathology, Filaggrin Proteins, Heat-Shock Proteins metabolism, Humans, Keratinocytes cytology, Keratinocytes metabolism, Keratins metabolism, Molecular Chaperones metabolism, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, RNA Interference, RNA, Small Interfering metabolism, Rats, Thiazolidines pharmacology, Actins metabolism, Epidermis metabolism, Intermediate Filament Proteins metabolism, Organogenesis drug effects
- Abstract
Epidermal stratification critically depends on keratinocyte differentiation and programmed death by cornification, leading to formation of a protective skin barrier. Cornification is dynamically controlled by the protein filaggrin, rapidly released from keratohyalin granules (KHGs). However, the mechanisms of cornification largely remain elusive, partly due to limitations of the observation techniques employed to study filaggrin organization in keratinocytes. Moreover, while the abundance of keratins within KHGs has been well described, it is not clear whether actin also contributes to their formation or fate. We employed advanced (super-resolution) microscopy to examine filaggrin organization and dynamics in skin and human keratinocytes during differentiation. We found that filaggrin organization depends on the cytoplasmic actin cytoskeleton, including the role for α- and β-actin scaffolds. Filaggrin-containing KHGs displayed high mobility and migrated toward the nucleus during differentiation. Pharmacological disruption targeting actin networks resulted in granule disintegration and accelerated cornification. We identified the role of AKT serine/threonine kinase 1 (AKT1), which controls binding preference and function of heat shock protein B1 (HspB1), facilitating the switch from actin stabilization to filaggrin processing. Our results suggest an extended model of cornification in which filaggrin utilizes actins to effectively control keratinocyte differentiation and death, promoting epidermal stratification and formation of a fully functional skin barrier.
- Published
- 2018
- Full Text
- View/download PDF
31. Therapeutic vaccines for allergic disease.
- Author
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Gutowska-Owsiak D and Ogg GS
- Abstract
Allergic diseases are highly prevalent worldwide and affect all age groups, contributing to a high personal and socioeconomic burden. Treatment with an "allergy vaccine" or allergen immunotherapy aims to provide long-lasting benefits by inducing unresponsiveness to the relevant antigen. The consequences of the therapy are considered disease modifying and range from dampening of the immediate immune responses to the reduction of secondary tissue remodeling. Furthermore, allergen immunotherapy interventions have a potential to slow or cease the development of additional allergic manifestations with a long-term overall effect on morbidity and quality of life. Here, we review proposed mechanisms underlying the therapeutic effects of immunotherapy for allergic diseases. Further, we discuss both standard and novel approaches and possible future directions in the development of allergen immunotherapy., Competing Interests: The authors declare no competing interests.
- Published
- 2017
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32. Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.
- Author
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Cheung KL, Jarrett R, Subramaniam S, Salimi M, Gutowska-Owsiak D, Chen YL, Hardman C, Xue L, Cerundolo V, and Ogg G
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- Case-Control Studies, Clathrin metabolism, Cohort Studies, Cytosol metabolism, Endocytosis, Humans, K562 Cells, Lymphocyte Activation immunology, Psoriasis blood, Psoriasis enzymology, Psoriasis pathology, Skin pathology, Antigen Presentation immunology, Antigens, CD1 metabolism, Exosomes metabolism, Group IV Phospholipases A2 immunology, Lipids immunology, Mast Cells enzymology, Psoriasis immunology, T-Lymphocytes immunology
- Abstract
Psoriasis is a chronic inflammatory skin disease associated with a T helper 17 response. Yet, it has proved challenging to identify relevant peptide-based T cell antigens. Antigen-presenting Langerhans cells show a differential migration phenotype in psoriatic lesions and express constitutively high levels of CD1a, which presents lipid antigens to T cells. In addition, phospholipase A
2 (PLA2 ) is highly expressed in psoriatic lesions and is known to generate neolipid skin antigens for recognition by CD1a-reactive T cells. In this study, we observed expression of a cytoplasmic PLA2 (PLA2G4D) in psoriatic mast cells but, unexpectedly, also found PLA2G4D activity to be extracellular. This was explained by IFN-α-induced mast cell release of exosomes, which transferred cytoplasmic PLA2 activity to neighboring CD1a-expressing cells. This led to the generation of neolipid antigens and subsequent recognition by lipid-specific CD1a-reactive T cells inducing production of IL-22 and IL-17A. Circulating and skin-derived T cells from patients with psoriasis showed elevated PLA2G4D responsiveness compared with healthy controls. Overall, these data present an alternative model of psoriasis pathogenesis in which lipid-specific CD1a-reactive T cells contribute to psoriatic inflammation. The findings suggest that PLA2 inhibition or CD1a blockade may have therapeutic potential for psoriasis., (© 2016 Cheung et al.)- Published
- 2016
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33. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.
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Jarrett R, Salio M, Lloyd-Lavery A, Subramaniam S, Bourgeois E, Archer C, Cheung KL, Hardman C, Chandler D, Salimi M, Gutowska-Owsiak D, de la Serna JB, Fallon PG, Jolin H, Mckenzie A, Dziembowski A, Podobas EI, Bal W, Johnson D, Moody DB, Cerundolo V, and Ogg G
- Subjects
- Adolescent, Adult, Aged, Animals, Cell Separation, Cytokines metabolism, Dermatitis, Atopic blood, Dermatitis, Atopic immunology, Filaggrin Proteins, Humans, K562 Cells, Middle Aged, Pyroglyphidae drug effects, Skin immunology, Skin pathology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Young Adult, Antigens, CD1 metabolism, Group IV Phospholipases A2 metabolism, Intermediate Filament Proteins pharmacology, Pyroglyphidae enzymology
- Abstract
Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation contribute to pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and although Langerhans cells expressing the nonclassical major histocompatibility complex (MHC) family member CD1a are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. We observed that house dust mite (HDM) allergen generates neolipid antigens presented by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth in individuals with atopic dermatitis and showed rapid effector function, consistent with antigen-driven maturation. In HDM-challenged human skin, we observed phospholipase A2 (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2, and such cells infiltrated the skin after allergen challenge. Moreover, we observed that the skin barrier protein filaggrin, insufficiency of which is associated with atopic skin disease, inhibited PLA2 activity and decreased CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity suggest that nonpeptide stimulants of T cells act as haptens that modify peptides or proteins; however, our results show that HDM proteins may also generate neolipid antigens that directly activate T cells. These data define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
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34. Platelet activating factor contributes to vascular leak in acute dengue infection.
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Jeewandara C, Gomes L, Wickramasinghe N, Gutowska-Owsiak D, Waithe D, Paranavitane SA, Shyamali NL, Ogg GS, and Malavige GN
- Subjects
- Adult, Cells, Cultured, Communicable Diseases pathology, Down-Regulation, Electric Impedance, Female, Human Umbilical Vein Endothelial Cells, Humans, Male, Neglected Diseases pathology, Platelet Membrane Glycoproteins antagonists & inhibitors, Receptors, G-Protein-Coupled antagonists & inhibitors, Capillary Permeability physiology, Platelet Activating Factor metabolism, Severe Dengue pathology, Tight Junctions pathology, Zonula Occludens-1 Protein blood
- Abstract
Background: Although plasma leakage is the hallmark of severe dengue infections, the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF) is associated with an increase in vascular permeability in other diseases, we set out to investigate its role in acute dengue infection., Materials and Methods: PAF levels were initially assessed in 25 patients with acute dengue infection to determine if they were increased in acute dengue. For investigation of the kinetics of PAF, serial PAF values were assessed in 36 patients. The effect of dengue serum on tight junction protein ZO-1 was determined by using human endothelial cell lines (HUVECs). The effect of dengue serum on and trans-endothelial resistance (TEER) was also measured on HUVECs., Results: PAF levels were significantly higher in patients with acute dengue (n = 25; p = 0.001) when compared to healthy individuals (n = 12). In further investigation of the kinetics of PAF in serial blood samples of patients (n = 36), PAF levels rose just before the onset of the critical phase. PAF levels were significantly higher in patients with evidence of vascular leak throughout the course of the illness when compared to those with milder disease. Serum from patients with dengue significantly down-regulated expression of tight junction protein, ZO-1 (p = 0.004), HUVECs. This was significantly inhibited (p = 0.004) by use of a PAF receptor (PAFR) blocker. Serum from dengue patients also significantly reduced TEER and this reduction was also significantly (p = 0.02) inhibited by prior incubation with the PAFR blocker., Conclusion: Our results suggest the PAF is likely to be playing a significant role in inducing vascular leak in acute dengue infection which offers a potential target for therapeutic intervention.
- Published
- 2015
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35. Filaggrin-insufficiency in keratinocytes influences responsiveness of allergen-specific T cells to cognate antigen and compounds barrier function deficiency.
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Marwah I, Wang X, Chan H, Ogg GS, and Gutowska-Owsiak D
- Subjects
- Filaggrin Proteins, Humans, Intermediate Filament Proteins deficiency, Skin immunology, Skin metabolism, Skin pathology, Allergens immunology, Intermediate Filament Proteins genetics, Keratinocytes metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Published
- 2014
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- View/download PDF
36. Proliferatory defect of invariant population and accumulation of non-invariant CD1d-restricted natural killer T cells in the joints of RA patients.
- Author
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Gutowska-Owsiak D, Birchall MA, Moots RJ, Christmas SE, and Pazmany L
- Subjects
- Arthritis, Rheumatoid metabolism, Arthritis, Rheumatoid pathology, CD4 Antigens metabolism, Cell Proliferation, Cytokines metabolism, Humans, Joints metabolism, Joints pathology, Natural Killer T-Cells metabolism, Natural Killer T-Cells pathology, Synovial Fluid immunology, Synovial Fluid metabolism, Arthritis, Rheumatoid immunology, Joints immunology, Natural Killer T-Cells immunology
- Abstract
Objectives: While numerical and functional defects of invariant NKT cells have been demonstrated in rheumatoid arthritis (RA), the detailed characterization of proliferative and secretory responses following CD1d-mediated presentation is lacking; the presence of non-invariant populations has never been assessed in human autoimmunity. We have evaluated both invariant and non-invariant populations in the blood and synovial fluid from patients to assess feasibility of NKT cell-directed manipulations in RA., Methods: NKT cell populations were quantified by anti-CD4/anti-Vα24 staining and/or CD1d tetramers. Proliferation was measured in cultures of mononuclear cells following stimulations with αGalCer and cytokine secretion determined by multi-bead assay., Results: We have confirmed a proliferative defect of iNKT cells in both peripheral blood and synovial fluid from RA patients, but no changes in baseline frequencies. Moreover, we have detected an enlargement of non-invariant cell pool in synovial fluid samples. In addition, we noted an evident Th2 shift following exposure to αGalCer and pronounced IL-6 secretion., Conclusions: While RA patients suffer from defective proliferative responses of invariant NKT cells, non-invariant cells accumulate at the site of inflammation. While stimulation with αGalCer results in reduced TNF-α and increased suppressive IL-10, abundantly produced IL-6 could potentially contribute to the induction of Th17 cells in the joints.
- Published
- 2014
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37. Expanded population of CD1d-restricted Vα24+ cells in a patient with active rheumatoid arthritis.
- Author
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Gutowska-Owsiak D, Birchall MA, Moots RJ, Christmas SE, and Pazmany L
- Subjects
- Female, Humans, Diabetes Mellitus, Type 1 immunology, Natural Killer T-Cells immunology
- Published
- 2014
- Full Text
- View/download PDF
38. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis.
- Author
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Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, Huang LC, Johnson D, Scanlon ST, McKenzie AN, Fallon PG, and Ogg GS
- Subjects
- Allergens chemistry, Animals, Cadherins metabolism, Cell Differentiation, Cell Separation, Cytokines metabolism, Dermatitis, Atopic immunology, Filaggrin Proteins, Flow Cytometry, Humans, Inflammation, Interleukin-13 metabolism, Interleukin-33, Interleukin-5 metabolism, Intermediate Filament Proteins metabolism, Leukocytes cytology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Phenotype, Skin metabolism, Dermatitis, Atopic metabolism, Interleukin-17 metabolism, Interleukins metabolism, Lymphocytes cytology
- Abstract
Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1(-/-) and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.
- Published
- 2013
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- View/download PDF
39. The epidermis as an adjuvant.
- Author
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Gutowska-Owsiak D and Ogg GS
- Subjects
- Dermatitis therapy, Humans, Dermatitis immunology, Epidermis immunology, Immune System immunology, Keratinocytes immunology
- Abstract
It is now clear that the epidermis has an active role in local immune responses in the skin. Keratinocytes are involved early in inflammation by providing first-line innate mechanisms and, in addition, can contribute to adaptive immune responses that may be associated with clinical disease. Moreover, keratinocytes are capable of enhancing and shaping the outcome of inflammation in response to stimuli and promoting particular types of immune bias. Through understanding the underlying mechanisms, the role of keratinocytes in disease pathogenesis will be further defined, which is likely to lead to the identification of potential targets for prophylactic or therapeutic intervention.
- Published
- 2012
- Full Text
- View/download PDF
40. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion.
- Author
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Gutowska-Owsiak D, Schaupp AL, Salimi M, Selvakumar TA, McPherson T, Taylor S, and Ogg GS
- Subjects
- Cadherins genetics, Cadherins metabolism, Calpain genetics, Cathepsin B genetics, Cathepsin D genetics, Cathepsin L genetics, Cell Differentiation genetics, Cell Line, Cells, Cultured, Claudins genetics, Cytoskeletal Proteins genetics, Filaggrin Proteins, Gene Expression genetics, Humans, Intermediate Filament Proteins genetics, Keratinocytes drug effects, Membrane Proteins genetics, Membrane Proteins metabolism, Oligonucleotide Array Sequence Analysis, Phosphoproteins genetics, Phosphoproteins metabolism, S100 Proteins genetics, Up-Regulation genetics, Zonula Occludens-1 Protein, Zonula Occludens-2 Protein, gamma Catenin genetics, gamma Catenin metabolism, Cell Adhesion Molecules genetics, Down-Regulation genetics, Gene Expression drug effects, Interleukin-17 pharmacology, Intermediate Filament Proteins metabolism, Keratinocytes metabolism
- Abstract
Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target., (© 2011 John Wiley & Sons A/S.)
- Published
- 2012
- Full Text
- View/download PDF
41. Immunologic response of the laryngeal mucosa to extraesophageal reflux.
- Author
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Birchall MA, Bailey M, Gutowska-Owsiak D, Johnston N, Inman CF, Stokes CR, Postma G, Pazmany L, Koufman JA, Phillips A, and Rees LE
- Subjects
- Adult, Antigens, CD1d metabolism, Biopsy, Case-Control Studies, Female, Fluorescent Antibody Technique, Globosides metabolism, Histocompatibility Antigens metabolism, Humans, Killer Cells, Natural metabolism, Larynx pathology, Male, Middle Aged, NK Cell Lectin-Like Receptor Subfamily B metabolism, Prospective Studies, Trihexosylceramides metabolism, Gastroesophageal Reflux immunology, Laryngeal Mucosa immunology, Laryngeal Mucosa metabolism
- Abstract
Objectives: Extraesophageal reflux is common. The treatment costs are high, and there are associations with other diseases, including laryngeal cancer. Our studies of the mucosal immune response to this common inflammatory disease suggest an important role for the nonclassic antigen-presenting molecule CD1d in the response to inflammation. This study was performed to further explore the relationship between the CD1d-NKT cell-iGb3 axis and reflux., Methods: We carried out a prospective study of laryngeal biopsies from 12 patients with laryngopharyngeal reflux and 11 controls. Quantitative multiple-color immunofluorescence using antibodies for lymphocytes (CD3, CD161) and classic and nonclassic major histocompatibility complex (I, II, beta2m, CD1d) was performed, and univariate and multivariate analysis and co-localization measurements were applied., Results: Epithelial major histocompatibility complex class I and II expression was unchanged by reflux, but expression of CD1d increased (p < 0.05; luminal layers) and confidence intervals diminished in the reflux group. Co-localization of NKT cells with CD1d increased in patients (p < 0.01); iGb3 exhibited strong expression throughout all layers of the laryngeal epithelium., Conclusions: These data indicate a role for the CD1d-NKT cell-iGb3 axis in response to extraesophageal reflux in humans. This represents a useful target for novel diagnostics and treatments for this common condition.
- Published
- 2008
- Full Text
- View/download PDF
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