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Immunologic diseases. Allergy and RC581-607

Type I interferon kappa (IFNκ) is selectively expressed in human keratinocytes. Herpes simplex virus-1 (HSV-1) is a human pathogen that infects keratinocytes and causes lytic skin lesions. Whether IFNκ plays a role in keratinocyte host defense against HSV-1 has not been investigated. In this study, we found that IFNκ mRNA expression was induced by addition of recombinant IFNκ and poly (I:C); and its expression level was significantly greater than IFNa2, IFNb1, and IFNL1 in both undifferentiated and differentiated normal human epidermal keratinocytes (NHEKs) under resting and stimulation conditions. Although IFNe was expressed at a relatively higher level than other IFNs in resting undifferentiated NHEK, its expression level did not change after stimulation with recombinant IFNκ and poly (I:C). HSV-1 infection inhibited gene expression of IFNκ and IFNe in NHEK. Silencing IFNκ in NHEK led to significantly enhanced HSV-1 replication in both undifferentiated and differentiated NHEK compared to scrambled siRNA-transfected cells, while the addition of recombinant IFNκ significantly reduced HSV-1 replication in NHEK. In addition, we found that IFNκ did not regulate protein expression of NHEK differentiation markers. Our results demonstrate that IFNκ is the dominant type of IFNs in keratinocytes and it has an important function for keratinocytes to combat HSV-1 infection.

Medicine and Science

[This corrects the article DOI: 10.1371/journal.pone.0167392.].

Immunologic diseases. Allergy and RC581-607

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

Medicine and Science

The epidermis serves as a critical protective barrier between the internal and external environment of the human body. Its remarkable barrier function is established through the keratinocyte (KC) terminal differentiation program. The transcription factors specifically regulating terminal differentiation remain largely unknown. Using a RNA-sequencing (RNA-seq) profiling approach, we found that forkhead box c 1 (FOXC1) was significantly up-regulated in human normal primary KC during the course of differentiation. This observation was validated in human normal primary KC from several different donors and human skin biopsies. Silencing FOXC1 in human normal primary KC undergoing differentiation led to significant down-regulation of late terminal differentiation genes markers including epidermal differentiation complex genes, keratinization genes, sphingolipid/ceramide metabolic process genes and epidermal specific cell-cell adhesion genes. We further demonstrated that FOXC1 works down-stream of ZNF750 and KLF4, and upstream of GRHL3. Thus, this study defines FOXC1 as a regulator specific for KC terminal differentiation and establishes its potential position in the genetic regulatory network.

Dermatology, Dermatologie, Immunology, immunopathology, allergology, Immunologie, immunopathologie, allergologie, Pneumology, Pneumologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Immunologie fondamentale, Fundamental immunology, Sciences medicales, Medical sciences, Pathologie infectieuse, Infectious diseases, Viroses, Viral diseases, Viroses humaines, Human viral diseases, Viroses avec lésions cutanées ou muqueuses et viroses oculaires, Viral diseases with cutaneous or mucosal lesions and viral diseases of the eye, Immunopathologie, Immunopathology, Maladies allergiques, Allergic diseases, Dermatoses allergiques. Allergie aux piqûres d'insectes, Skin allergic diseases. Stinging insect allergies, Sarcoidoses. Granulomatoses d'etiologie indeterminee. Maladies du tissu conjonctif. Maladies du tissu elastique. Vascularites, Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis, Allergie, Allergy, Alergia, Alphaherpesvirinae, Atopie, Atopy, Atopía, Cytokine, Citoquina, Dermatose pustuleuse, Pustulosis dermatosis, Dermatosis pustulosa, Herpesviridae, Infection, Infección, Pathologie de la peau, Skin disease, Piel patología, Virose, Viral disease, Virosis, Virus, Complication, Complicación, Dermatite atopique, Atopic dermatitis, Dermatitis atópica, Herpesvirus hominis, Herpès, Herpes, Homme, Human, Hombre, Identification, Identificación, Immunologie, Immunology, Inmunología, Immunopathologie, Immunopathology, Inmunopatología, Interféron, Interferon, Interferón, Pustulose varioliforme de Kaposi-Juliusberg, Kaposi-Juliusberg syndrome, Pustulosis varioliforme Kaposi-Juliusberg, Facteur de régulation de l'interféron, Interferon regulatory factor, Facteur de régulation de linterféron 3, Interferon regulatory factor 3, Profil d'expression génique, Gene expression profile, Perfil de expresión genética, eczema herpeticum, herpes simplex virus, interferon regulatory factor 3, interferon regulatory factor 7, type I interferon, and type III interferon

Background: A subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection (ie, atopic dermatitis with a history of eczema herpeticum [ADEH+]). Biomarkers that identify ADEH+ are lacking. Objective: We sought to search for novel ADEH+ gene signatures in PBMCs. Methods: An RNA-sequencing approach was applied to evaluate global transcriptional changes by using PBMCs from patients with ADEH+ and patients with atopic dermatitis without a history of eczema herpeticum (ADEH-). Candidate genes were confirmed by means of quantitative PCR or ELISA. Results: PBMCs from patients with ADEH+ had distinct changes to the transcriptome when compared with those from patients with ADEH- after HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate of less than 0.05 (ANOVA), and 15 type I and type III interferon genes were among the top 20 most downregulated genes in patients with ADEH+. We further validated that IFN-α and IL-29 mRNA and protein levels were significantly decreased in HSV-1-stimulated PBMCs from patients with ADEH+ compared with those from patients with ADEH- and healthy subjects. Ingenuity Pathway Analysis demonstrated that the upstream regulators of type I and type III interferons, interferon regulatory factor (IRF) 3 and IRF7, were significantly inhibited in patients with ADEH+ based on the downregulation of their target genes. Furthermore, we found that gene expression of IRF3 and IRF7 was significantly decreased in HSV-1-stimulated PBMCs from patients with ADEH+. Conclusions: PBMCs from patients with ADEH+ have a distinct immune response after HSV-1 exposure compared with those from patients with ADEH-. Inhibition of the IRF3 and IRF7 innate immune pathways in patients with ADEH+ might be an important mechanism for increased susceptibility to disseminated viral infection.

Dermatology, Dermatologie, Immunology, immunopathology, allergology, Immunologie, immunopathologie, allergologie, Pneumology, Pneumologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Immunologie fondamentale, Fundamental immunology, Sciences medicales, Medical sciences, Pathologie infectieuse, Infectious diseases, Bactérioses, Bacterial diseases, Bactérioses humaines, Human bacterial diseases, Staphylococcies, streptococcies, pneumococcies, Staphylococcal infections, streptococcal infections, pneumococcal infections, Immunopathologie, Immunopathology, Maladies allergiques, Allergic diseases, Dermatoses allergiques. Allergie aux piqûres d'insectes, Skin allergic diseases. Stinging insect allergies, Sarcoidoses. Granulomatoses d'etiologie indeterminee. Maladies du tissu conjonctif. Maladies du tissu elastique. Vascularites, Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis, Allergie, Allergy, Alergia, Atopie, Atopy, Atopía, Bactérie, Bacteria, Bactériose, Bacteriosis, Enzyme, Enzima, Esterases, Hydrolases, Infection, Infección, Micrococcaceae, Micrococcales, Pathologie de la peau, Skin disease, Piel patología, Phosphoric diester hydrolases, Dermatite atopique, Atopic dermatitis, Dermatitis atópica, Filaggrine, Filaggrin, Filagrina, Immunologie, Immunology, Inmunología, Immunopathologie, Immunopathology, Inmunopatología, Kératinocyte, Keratinocyte, Queratinocito, Mort, Death, Muerte, Mortalité, Mortality, Mortalidad, Peau, Skin, Piel, Protection, Protección, Sphingomyelin phosphodiesterase, Staphylococcie, Staphylococcal infection, Estafilococia, Staphylococcus aureus, Sécrétion, Secretion, Secreción, Toxine, Toxin, Toxina, acid sphingomyelinase, filaggrin, skin barrier, and α-toxin

Background: The skin of patients with atopic dermatitis (AD) has defects in keratinocyte differentiation, particularly in expression of the epidermal barrier protein filaggrin. AD skin lesions are often exacerbated by Staphylococcus aureus― mediated secretion of the virulence factor α-toxin. It is unknown whether lack of keratinocyte differentiation predisposes to enhanced lethality from staphylococcal toxins. Objective: We investigated whether keratinocyte differentiation and filaggrin expression protect against cell death induced by staphylococcal α-toxin. Methods: Filaggrin-deficient primary keratinocytes were generated through small interfering RNA gene knockdown. RNA expression was determined by using real-time PCR. Cell death was determined by using the lactate dehydrogenase assay. Keratinocyte cell survival in filaggrin-deficient (ft/ft) mouse skin biopsies was determined based on Keratin 5 staining. α-Toxin heptamer formation and acid sphingomyelinase expression were determined by means of immunoblotting. Results: We found that filaggrin expression, occurring as the result of keratinocyte differentiation, significantly inhibits staphylococcal α-toxin―mediated pathogenicity. Furthermore, filaggrin plays a crucial role in protecting cells by mediating the secretion of sphingomyelinase, an enzyme that reduces the number of α-toxin binding sites on the keratinocyte surface. Finally, we determined that sphingomyelinase enzymatic activity directly prevents α-toxin binding and protects keratinocytes against α-toxin―induced cytotoxicity. Conclusions: The current study introduces the novel concept that S aureus α-toxin preferentially targets and destroys filaggrin-deficient keratinocytes. It also provides a mechanism to explain the increased propensity for S aureus―mediated exacerbation of AD skin disease.

Dermatology, Dermatologie, Immunology, immunopathology, allergology, Immunologie, immunopathologie, allergologie, Pneumology, Pneumologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Immunologie fondamentale, Fundamental immunology, Sciences medicales, Medical sciences, Pathologie infectieuse, Infectious diseases, Viroses, Viral diseases, Immunopathologie, Immunopathology, Maladies allergiques, Allergic diseases, Dermatoses allergiques. Allergie aux piqûres d'insectes, Skin allergic diseases. Stinging insect allergies, Sarcoidoses. Granulomatoses d'etiologie indeterminee. Maladies du tissu conjonctif. Maladies du tissu elastique. Vascularites, Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis, Allergie, Allergy, Alergia, Alphaherpesvirinae, Atopie, Atopy, Atopía, Bactérie, Bacteria, Chordopoxvirinae, Herpesviridae, Infection, Infección, Micrococcaceae, Micrococcales, Orthopoxvirus, Pathologie de la peau, Skin disease, Piel patología, Poxviridae, Virus, Dermatite atopique, Atopic dermatitis, Dermatitis atópica, Herpesvirus hominis, Immunologie, Immunology, Inmunología, Immunopathologie, Immunopathology, Inmunopatología, Peau, Skin, Piel, Réponse immune, Immune response, Respuesta inmune, Staphylococcus aureus, Toxine, Toxin, Toxina, Virose, Viral disease, Virosis, Virus vaccine, Vaccinia virus, Désintégrine, Disintegrin, Desintegrina, a disintegrin and metalloprotease 10, herpes simplex virus, vaccinia virus, and α-toxin

Background: Patients with atopic dermatitis (AD) with a history of eczema herpeticum have increased staphylococcal colonization and infections. However, whether Staphylococcus aureus alters the outcome of skin viral infection has not been determined. Objective: We investigated whether S aureus toxins modulated host response to herpes simplex virus (HSV) 1 and vaccinia virus (VV) infections in normal human keratinocytes (NHKs) and in murine infection models. Methods: NHKs were treated with S aureus toxins before incubation of viruses. BALB/c mice were inoculated with S aureus 2 days before VV scarification. Viral loads of HSV-1 and VV were evaluated by using real-time PCR, a viral plaque-forming assay, and immunofluorescence staining. Small interfering RNA duplexes were used to knockdown the gene expression of the cellular receptor of α-toxin, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 protein and α-toxin heptamers were detected by using Western blot assays. Results: We demonstrate that sublytic staphylococcal α-toxin increases viral loads of HSV-1 and VV in NHKs. Furthermore, we demonstrate in vivo that the VV load is significantly greater (P <.05) in murine skin inoculated with an α-toxin―producing S aureus strain compared with murine skin inoculated with the isogenic α-toxin―deleted strain. The viral enhancing effect of α-toxin is mediated by ADAM10 and is associated with its pore-forming property. Moreover, we demonstrate that α-toxin promotes viral entry in NHKs. Conclusion: The current study introduces the novel concept that staphylococcal α-toxin promotes viral skin infection and provides a mechanism by which S aureus infection might predispose the host toward disseminated viral infections.

Dermatology, Dermatologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Dermatologie, Dermatology, Dermatologie, Dermatology, Dermatología, Expression génique, Gene expression, Expresión genética, Facteur transcription, Transcription factor, Factor transcripción, Kératinocyte, Keratinocyte, Queratinocito, Protéine, Protein, Proteína, Spécificité, Specificity, Especificidad, Thymus, Thymus gland, Timo, and Kallikrein

Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsy samples obtained from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in skin biological processes by using a small-interfering RNA (siRNA) technique to knock down Sp1 gene expression in normal human keratinocytes (NHKs) and investigated the genome-wide gene expression profiling of Sp1-silenced NHKs. The gene arrays revealed that 53 genes had greater than 3-fold changes in the expression in Sp1-silenced NHKs as compared with scrambled siRNA-silenced cells. Strikingly, six kallikrein (KLK)-related peptidase genes, namely KLK5, KLK6, KLK7, KLK8, KLK10, and KLK12, were upregulated in NHKs following Sp1 silencing. Functionally, protease activity was significantly enhanced in Sp1-silenced keratinocytes as compared with scrambled siRNA-silenced keratinocytes. Moreover, thymic stromal lymphopoietin (TSLP), an epithelial-derived TH2-promoting cytokine, was induced in Sp1-silenced keratinocytes because of elevated KLK activity. These results indicate that Sp1 expression deficiency leads to abnormally increased KLK protease activity in keratinocytes and may contribute to TH2 immune responses in the skin by inducing TSLP.

Medical oncology, Cancérologie, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Anticancéreux, Antineoplastic agents, Tumeurs, Tumors, Cytokine, Citoquina, Facteur nécrose tumorale, Tumor necrosis factor, Factor necrosis tumoral, Inhibiteur du protéasome, Proteasome inhibitor, Inhibidor proteasome, Ligand TRAIL, TNF related apoptosis inducing ligand, Ligando TRAIL, Mécanisme action, Mechanism of action, Mecanismo acción, Résistance, Resistance, and Resistencia

One impediment to the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-targeted agents as antitumor drugs is the evolution of resistance, a common problem in cancer. On the contrary, many different kinds of drugs synergize with TRAIL in TRAIL-sensitive tumor cells, raising the question whether one can overcome resistance with the same drugs producing synergy. This is an important question, because recent clinical trials suggest that combination treatments with cytotoxic drugs and TRAIL receptor-targeted agents do not provide additional benefit compared with cytotoxic agents on their own. Such results might be expected if drug combinations that synergize in sensitive tumor cells but cannot overcome TRAIL resistance are used in patients whose tumors were not selected for retention of TRAIL sensitivity. We tested this idea by creating isogenic tumor cells with acquired TRAIL resistance or defined mechanisms of resistance that occur in human tumors and then comparing them to the TRAIL-sensitive parental cell line. Although diverse classes of anticancer drugs were all able to synergize with TRAIL in sensitive cells, most agents were unable to overcome resistance and there was no relationship between the amount of synergy seen with a particular agent and its ability to overcome acquired resistance. An important exception was proteasome inhibitors, which were, however, able to overcome diverse resistance mechanisms. Our findings suggest that one should select drugs for TRAIL receptor agonist combination therapy based not just on their ability to synergize, but rather on their ability to overcome resistance as well as synergize.

Dermatology, Dermatologie, Immunology, immunopathology, allergology, Immunologie, immunopathologie, allergologie, Pneumology, Pneumologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Immunologie fondamentale, Fundamental immunology, Sciences medicales, Medical sciences, Immunopathologie, Immunopathology, Maladies allergiques, Allergic diseases, Dermatoses allergiques. Allergie aux piqûres d'insectes, Skin allergic diseases. Stinging insect allergies, Sarcoidoses. Granulomatoses d'etiologie indeterminee. Maladies du tissu conjonctif. Maladies du tissu elastique. Vascularites, Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis, Allergie, Allergy, Alergia, Atopie, Atopy, Atopía, Chordopoxvirinae, Cytokine, Citoquina, Orthopoxvirus, Pathologie de la peau, Skin disease, Piel patología, Poxviridae, Virus, Dermatite atopique, Atopic dermatitis, Dermatitis atópica, Expression génique, Gene expression, Expresión genética, Immunologie, Immunology, Inmunología, Immunopathologie, Immunopathology, Inmunopatología, Inhibiteur, Inhibitor, Inhibidor, Inhibition, Inhibición, Interleukine 10, Interleukin 10, Interleuquina 10, Interleukine 2, Interleukin 2, Interleuquina 2, Kératinocyte, Keratinocyte, Queratinocito, Récepteur biologique, Biological receptor, Receptor biológico, Virus vaccine, Vaccinia virus, Interféron lambda, Lambda interferon, IFN-λ, IL-10 receptor, IL-29, SIOOA11, atopic dermatitis, and vaccinia virus

Background: The mechanism that predisposes patients with atopic dermatitis (AD) to disseminated vaccinia viral (VV) skin infection after smallpox vaccination is unknown. We have demonstrated that expression of S100A11, a calcium-binding protein involved in keratinocyte differentiation, is downregulated in AD. Objective: We investigated whether inhibiting expression of S100A11 increased VV replication in human keratinocytes and the mechanism by which S100A11 affects the innate immune response of keratinocytes. Methods: Small interfering RNA duplexes were used to reduce gene expression of S100A11 in keratinocytes. VV replication was evaluated by real-time PCR and viral plaque assay. VV cytopathic effect was assessed by crystal violet staining. Affymetrix GeneChip assay was used to compare gene expression profiles. Real time PCR, Western blotting, and immunohistochemistry staining assay were used to evaluate gene expression in keratinocytes and AD skin biopsies. Results: Keratinocytes with deficient S100A11 expression supported increased VV replication and manifested augmented VV cytopathic effects. Gene microarray analysis revealed that the IL-10 receptor 2 chain (IL-10R2), which binds IFN-λs, was downregulated by 2.26-fold in S100A11-silenced keratinocytes. IL-10R2 expression was found to be decreased in skin biopsies from patients with acute AD (mean, 25.21 ± 5.25; n = 20) compared with skin from normal healthy subjects (mean, 137.1 ± 34.46; n = 19; P < .01). Furthermore, deficient S100A11 gene expression significantly impaired IL-29 (IFN-λ1) responsiveness (2' 5'-oligoadenylate synthetase and Myxovirus [influenza virus] resistance induction) and its anti-VV effects in keratinocytes. Conclusions: Inhibition of S100A11 gene expression impairs the ability of keratinocytes to control VV replication via downregulation of IFN-λ receptor IL-10R2.

Dermatology, Dermatologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Dermatologie, Dermatology, Cytodifférenciation, Cell differentiation, Diferenciación celular, Cytokine, Citoquina, Dermatologie, Dermatology, Dermatología, Inflammation, Inflamación, Kératinocyte, Keratinocyte, Queratinocito, Lymphocyte T, T-Lymphocyte, Linfocito T, Lymphocyte Th2, Th2 lymphocyte, and Linfocito Th2

Atopic dermatitis (AD) is an inflammatory skin disease associated with frequent skin infection and impaired skin barrier function. Recent studies indicate that increased Th2 cytokine expression contributes to reduction in antimicrobial peptides and reduced filaggrin (FLG) expression, however, the mechanisms leading to this effect is unknown. Using proteomics, we found the S100 calcium-binding protein A11 (S100/A11) to be significantly downregulated in the presence of IL-4 and IL-13. Culturing keratinocytes with increased calcium concentrations significantly induced S100/A11 expression. This corresponded with an increase in human β-defensin (HBD)-3 and FLG expression. Interference of S100/A11 expression, by siRNA, inhibited induction of HBD-3 and FLG. Furthermore p21, a cyclin-dependent kinase inhibitor downstream of S100/A11, was required for calcium-mediated induction of HBD-3 and FLG. Importantly, transduction of p21-recombinant protein into keratinocytes prevented IL-4/IL-13-mediated inhibition of FLG and HBD-3 expression. S100/A11 and p21 gene expression was also found to be significantly lower in acute and chronic AD skin. This study demonstrates an important role for S100/A11 and p21 in regulating skin barrier integrity and the innate immune response.