RESUMEN
The sphingolipid sphingosine-1-phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein-coupled receptors. The immune cell-specific sphingosine-1-phosphate receptor 4 (S1pr4) was connected to the generation of IL-17-producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod-induced murine psoriasis via regulation of IL-17 production. We did not observe altered IL-17 production, although psoriasis severity was reduced in S1pr4-deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL-6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and MÏ infiltration was also observed in Zymosan-A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident MÏs to produce CCL2, likely via the NF-κB pathway. We propose that S1pr4 activation enhances TLR response of resident MÏs to increase CCL2 production, which attracts further MÏs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.
Asunto(s)
Quimiocina CCL2/inmunología , Macrófagos/inmunología , Psoriasis/inmunología , Transducción de Señal/inmunología , Receptores de Esfingosina-1-Fosfato/inmunología , Animales , Quimiocina CCL2/genética , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Modelos Animales de Enfermedad , Granulocitos/inmunología , Granulocitos/patología , Interleucina-6/genética , Interleucina-6/inmunología , Macrófagos/patología , Ratones , Ratones Noqueados , Monocitos/inmunología , Monocitos/patología , Psoriasis/genética , Psoriasis/patología , Transducción de Señal/genética , Receptores de Esfingosina-1-Fosfato/genéticaRESUMEN
Tannins are eco-friendly, bio-sourced, natural, and highly reactive polyphenols. In the past decades, the understanding of their versatile properties has grown substantially alongside a continuously broadening of the tannins' application scope. In particular, recently, tannins have been increasingly investigated for their interaction with other species in order to obtain tannin-based hybrid systems that feature advanced and/or novel properties. Furthermore, in virtue of the tannins' chemistry and their high reactivity, they either physicochemically or physically interact with a wide variety of different compounds, including metals and ceramics, as well as a number of organic species. Such hybrid or hybrid-like systems allow the preparation of various advanced nanomaterials, featuring improved performances compared to the current ones. Consequently, these diverse-shaped materials have potential use in wastewater treatment or catalysis, as well as in some novel fields such as UV-shielding, functional food packaging, and biomedicine. Since these kinds of tannin-based hybrids represent an emerging field, thus far no comprehensive overview concerning their potential as functional chemical building blocks is available. Hence, this review aims to provide a structured summary of the current state of research regarding tannin-based hybrids, detailed findings on the chemical mechanisms as well as their fields of application.
Asunto(s)
Taninos/química , Animales , Humanos , Taninos/farmacologíaRESUMEN
We describe efficient synthetic routes to murrayamine A (mukoenine C), O-methylmurrayamine A, mahanine, O-methylmahanine, and murrayamine D and the first total syntheses of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction of the carbazole framework and an annulation of the pyran ring, which is either catalyzed by phenylboronic acid or promoted by a Lewis acid.
Asunto(s)
Alcaloides/química , Carbazoles/química , Carbazoles/síntesis química , Ácidos de Lewis/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
BACKGROUND: Sensitization to Hymenoptera venom without systemic sting reactions (SSRs) is commonly observed in the general population. Clinical relevance for a future sting has not yet been investigated. OBJECTIVE: We aimed to evaluate the effect of these debatable sensitizations with deliberate sting challenges and to monitor serologic changes for up to 2 years. METHODS: One hundred thirty-one challenges with bees and wasps were performed in 94 subjects with a hitherto irrelevant sensitization. The clinical outcome was recorded, and results of specific IgE (sIgE) determinations, skin tests, and basophil activation tests were correlated to the sting reaction. sIgE levels were monitored in reactors and nonreactors after 3 hours, 1 week, 4 weeks, and 1 year. RESULTS: Only 5 (5.3%) patients had SSRs, but 41 (43.6%) had large local reactions (LLRs) after the sting. Compared with the general population, there was a 9.5-fold higher risk for LLRs but not for SSRs. Three hours after the sting, sIgE levels slightly decreased, but none of the 94 subjects' results turned negative. After 1 week, sIgE levels already increased, increasing up to 3.5-fold (range, 0.2- to 34.0-fold) baseline levels after 4 weeks. To assess the clinical relevance of this increase, we randomly selected 18 patients for a re-sting. Again, 50% had an LLR, but none had an SSR. CONCLUSION: Although sensitization to Hymenoptera venoms was common, the risk of SSRs in sensitized subjects was low in our study. The sIgE level increase after the sting was not an indicator for conversion into symptomatic sensitization. Currently available tests were not able to distinguish between asymptomatic sensitization, LLRs, and SSRs.
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Alérgenos/inmunología , Venenos de Artrópodos/efectos adversos , Himenópteros/inmunología , Hipersensibilidad/inmunología , Mordeduras y Picaduras de Insectos/inmunología , Adulto , Animales , Femenino , Humanos , Hipersensibilidad/diagnóstico , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Mordeduras y Picaduras de Insectos/diagnóstico , Masculino , Evaluación del Resultado de la Atención al Paciente , Pruebas Cutáneas , Factores de Tiempo , Adulto JovenRESUMEN
Similar to all eczematous disorders, irritant and allergic contact dermatitis are primarily defined by their morphology. In addition, the diagnosis of this specific reaction pattern on the skin (and mucous membranes) also requires prior exposure (direct or indirect) to an allergen or irritant. While it is quite easy to give a textbook description of the typical features of eczema, its clinical manifestations in daily practice are diverse and frequently uncharacteristic. Contact reactions may present as lichenoid, lymphomatoid, granulomatous, pigmented, purpuric, and erythema multiforme-like lesions, thus lacking the typical eczematous appearance and broadening the spectrum of differential diagnoses to be considered. Moreover, a considerable number of agents, acting by mechanisms other than contact, may trigger adverse reactions mimicking the eczematic morphology and distribution pattern of contact dermatitis. Increasingly used in oncology, this is especially true for drugs such as kinase inhibitors. Knowledge of these associations is crucial for the adequate diagnostic and therapeutic care of patients with supposed or actual contact dermatitis.
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Dermatitis por Contacto/diagnóstico , Dermatitis por Contacto/terapia , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/terapia , Pruebas Cutáneas/métodos , Diagnóstico Diferencial , HumanosRESUMEN
A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.
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Biomarcadores/metabolismo , Enfermedades del Sistema Nervioso Central/diagnóstico , Espectroscopía de Resonancia Magnética/métodos , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/patología , HumanosRESUMEN
We propose a new figure of merit to assess the performance of light trapping nanostructures for solar cells, which we call the light trapping efficiency (LTE). The LTE has a target value of unity to represent the performance of an ideal Lambertian scatterer, although this is not an absolute limit but rather a benchmark value. Since the LTE aims to assess the nanostructure itself, it is, in principle, independent of the material, fabrication method or technology used. We use the LTE to compare numerous proposals in the literature and to identify the most promising light trapping strategies. We find that different types of photonic structures allow approaching the Lambertian limit, which shows that the light trapping problem can be approached from multiple directions. The LTE of theoretical structures significantly exceeds that of experimental structures, which highlights the need for theoretical descriptions to be more comprehensive and to take all relevant electro-optic effects into account.
RESUMEN
In Eµ-myc transgenic animals lymphoma formation requires additional genetic alterations, which frequently comprise loss of p53 or overexpression of BCL-2. We describe that the nature of the "second hit" affects the ability of the immune system to contain lymphoma development. Tumors with disrupted p53 signaling killed the host more rapidly than BCL-2 overexpressing ones. Relaxing immunologic control, using Tyk2(-/-) mice or by Ab-mediated depletion of CD8(+) T or natural killer (NK) cells accelerated formation of BCL-2-overexpressing lymphomas but not of those lacking p53. Most strikingly, enforced expression of BCL-2 prolonged disease latency in the absence of p53, whereas blocking p53 function in BCL-2-overexpressing tumors failed to accelerate disease. This shows that blocking apoptosis in p53-deficient cells by enforcing BCL-2 expression can mitigate disease progression increasing the "immunologic visibility." In vitro cytotoxicity assays confirmed that high expression of BCL-2 protein facilitates NK and T cell-mediated killing. Moreover, we found that high BCL-2 expression is accompanied by significantly increased levels of the NKG2D ligand MULT1, which may account for the enhanced killing. Our findings provide first evidence that the nature of the second hit affects tumor immunosurveillance in c-MYC-driven lymphomas and define a potential shortcoming of antitumor therapies targeting BCL-2.
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Epistasis Genética/inmunología , Genes myc/fisiología , Vigilancia Inmunológica/genética , Linfoma/genética , Mutación/fisiología , Animales , Transformación Celular Neoplásica/genética , Células Cultivadas , Progresión de la Enfermedad , Epistasis Genética/fisiología , Genes bcl-2/fisiología , Genes p53/fisiología , Linfoma/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , TYK2 Quinasa/genética , Escape del Tumor/genéticaRESUMEN
Thin film solar cells benefit significantly from the enhanced light trapping offered by photonic nanostructures. The thin film is typically patterned on one side only due to technological constraints. The ability to independently pattern both sides of the thin film increases the degrees of freedom available to the designer, as different functions can be combined, such as the reduction of surface reflection and the excitation of quasiguided modes for enhanced light absorption. Here, we demonstrate a technique based on simple layer transfer that allows us to independently pattern both sides of the thin film leading to enhanced light trapping. We used a 400 nm thin film of amorphous hydrogenated silicon and two simple 2D gratings for this proof-of-principle demonstration. Since the technique imposes no restrictions on the design parameters, any type of structure can be made.
RESUMEN
Ambient particulate matter (PM2.5) pollution is an important threat to human health. The aim of this study is to estimate the environmental burden of disease (EBD) for the German population associated with PM2.5 exposure in Germany for the years 2010 until 2018. The EBD method was used to quantify relevant indicators, e.g., disability-adjusted life years (DALYs), and the life table approach was used to estimate the reduction in life expectancy caused by long-term PM2.5 exposure. The impact of varying assumptions and input data was assessed. From 2010 to 2018 in Germany, the annual population-weighted PM2.5 concentration declined from 13.7 to 10.8 µg/m3. The estimates of annual PM2.5-attributable DALYs for all disease outcomes showed a downward trend. In 2018, the highest EBD was estimated for ischemic heart disease (101.776; 95% uncertainty interval (UI) 62,713-145,644), followed by lung cancer (60,843; 95% UI 43,380-79,379). The estimates for Germany differ from those provided by other institutions. This is mainly related to considerable differences in the input data, the use of a specific German national life expectancy and the selected relative risks. A transparent description of input data, computational steps, and assumptions is essential to explain differing results of EBD studies to improve methodological credibility and trust in the results. Furthermore, the different calculated indicators should be explained and interpreted with caution.
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Contaminantes Atmosféricos , Contaminación del Aire , Humanos , Material Particulado/efectos adversos , Material Particulado/análisis , Años de Vida Ajustados por Calidad de Vida , Esperanza de Vida , Contaminación Ambiental , Costo de Enfermedad , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. METHODS: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC. RESULTS: We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice. CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.
Asunto(s)
Colangitis Esclerosante/complicaciones , Citoprotección , Cirrosis Hepática Experimental/prevención & control , Factor de Transcripción STAT3/fisiología , Subfamilia B de Transportador de Casetes de Unión a ATP/fisiología , Animales , Ácidos y Sales Biliares/toxicidad , Proliferación Celular , Hígado/efectos de los fármacos , Regeneración Hepática , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Nanostructured metal assemblies on thin and ultrathin polymeric films enable state of the art technologies and have further potential in diverse fields. Rational design of the structure-function relationship is of critical importance but aggravated by the scarcity of systematic studies. Here, we studied the influence of the interplay between metal and polymer surface free energy and reactivity on the evolution of electric conductivity and the resulting morphologies. In situ resistance measurements during sputter deposition of Ag, Au, Cu and Ni films on ultrathin reticulated polymer films collectively reveal metal-insulator transitions characteristic for Volmer-Weber growth. The different onsets of percolation correlate with interfacial energy and energy of adhesion weakly but as expected from ordinary wetting theory. A more pronounced trend of lower percolation thickness for more reactive metals falls in line with reported correlations. Ex situ grazing incidence small angle X-ray scattering experiments were performed at various thicknesses to gain an insight into cluster and film morphology evolution. A novel approach to interpret the scattering data is used where simulated pair distance distributions of arbitrary shapes and arrangements can be fitted to experiments. Detailed approximations of cluster structures could be inferred and are discussed in view of the established parameters describing film growth behavior.
RESUMEN
The natural function of cellobiose dehydrogenase (CDH) to donate electrons from its catalytic flavodehydrogenase (DH) domain via its cytochrome (CYT) domain to lytic polysaccharide monooxygenase (LPMO) is an example of a highly efficient extracellular electron transfer chain. To investigate the function of the CYT domain movement in the two occurring electron transfer steps, two CDHs from the ascomycete Neurospora crassa (NcCDHIIA and NcCDHIIB) and five chimeric CDH enzymes created by domain swapping were studied in combination with the fungus' own LPMOs (NcLPMO9C and NcLPMO9F). Kinetic and electrochemical methods and hydrogen/deuterium exchange mass spectrometry were used to study the domain movement, interaction, and electron transfer kinetics. Molecular docking provided insights into the protein-protein interface, the orientation of domains, and binding energies. We find that the first, interdomain electron transfer step from the catalytic site in the DH domain to the CYT domain depends on steric and electrostatic interface complementarity and the length of the protein linker between both domains but not on the redox potential difference between the FAD and heme b cofactors. After CYT reduction, a conformational change of CDH from its closed state to an open state allows the second, interprotein electron transfer (IPET) step from CYT to LPMO to occur by direct interaction of the b-type heme and the type-2 copper center. Chimeric CDH enzymes favor the open state and achieve higher IPET rates by exposing the heme b cofactor to LPMO. The IPET, which is influenced by interface complementarity and the heme b redox potential, is very efficient with bimolecular rates between 2.9 × 105 and 1.1 × 106 M-1 s-1.
RESUMEN
Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL(+) human leukemic cells express PI3Kdelta and therefore explored its impact on leukemia development. Using PI3Kdelta-deficient mice, we define a dual role of PI3Kdelta in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell-mediated tumor surveillance: Abelson-transformed PI3Kdelta-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kdelta accelerated leukemia progression in vivo. However, the absence of PI3Kdelta also affected NK cell-mediated tumor surveillance. PI3Kdelta-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3Kdelta-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3Kdelta. Other tumor models confirmed that PI3Kdelta-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kdelta in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3Kdelta inhibitors as antileukemic agents in clinical trials.
Asunto(s)
Vigilancia Inmunológica/genética , Células Asesinas Naturales/inmunología , Leucemia/inmunología , Fosfatidilinositol 3-Quinasas/genética , Virus de la Leucemia Murina de Abelson/genética , Animales , Muerte Celular/genética , Muerte Celular/inmunología , Línea Celular Transformada , Fosfatidilinositol 3-Quinasa Clase I , Progresión de la Enfermedad , Regulación Leucémica de la Expresión Génica , Humanos , Células Jurkat , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Leucemia/genética , Leucemia/metabolismo , Leucemia/mortalidad , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/mortalidad , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Células Tumorales CultivadasRESUMEN
BACKGROUND: While the use of methyldibromo glutaronitrile (MDBGN) in leave-on products is clearly associated with high sensitization or elicitation risk, such a clear-cut relation could be questioned with regard to rinse-off products. OBJECTIVE: The objective of this study was to find a maximum non-eliciting concentration for rinse-off products in MDBGN patch test-positive patients. PATIENTS AND METHODS: We performed a use-related test [repeated open application test (ROAT)] in patients sensitized to MDBGN with a liquid soap containing three concentrations of MDBGN (50, 200, and 400 p.p.m. MDBGN, respectively). The soap at 50 p.p.m. was used twice daily for 4 weeks. If no reaction of the skin was observed, the product with the next higher concentration was used for another 4 weeks, etc. RESULTS: In total, 32/37 evaluated cases [86.5%; lower exact one-sided 95% confidence limit (CL): 73.7%] did not react to any of the preparations. The remaining reacted as follows: 1/37 reacted to 50 p.p.m., 3/37 to 200 p.p.m., and 1/37 to 400 p.p.m. The cumulative non-response to 50 p.p.m. was 97.3% (lower CL: 87.8%). CONCLUSIONS: The majority of subjects sensitized to MDBGN-tolerated rinse-off products containing a maximum concentration of 400 p.p.m. A concentration in rinse-off products in the range of 50 p.p.m. could be regarded as safe for most individuals already sensitized. These concentrations will presumably prevent induction (sensitization) also.
Asunto(s)
Dermatitis Alérgica por Contacto/etiología , Nitrilos/efectos adversos , Pruebas del Parche/efectos adversos , Conservadores Farmacéuticos/efectos adversos , Jabones/efectos adversos , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Piel/efectos de los fármacos , Adulto JovenRESUMEN
Responding to COVID-19 presents unprecedented challenges for public sector practitioners. Addressing those challenges requires knowledge about the problems that public sector workers face. This Viewpoint essay argues that timely, up-to-date surveys of public sector workers are essential tools for identifying problems, resolving bottlenecks, and enabling public sector workers to operate effectively during and in response to the challenges posed by the pandemic. This essay presents the COVID-19 Survey of Public Servants, which is currently being rolled out in several countries by the Global Survey of Public Servants Consortium to assist governments in strategically compiling evidence to operate effectively during the COVID-19 pandemic.
RESUMEN
BACKGROUND: The detection of specific serum immunoglobulin E (sIgE) to Hymenoptera venoms is an established diagnostic tool to diagnose insect venom hypersensitivity. However, the specificity of sIgE detection is a debated issue. METHODS: In 145 subjects, total IgE (tIgE) and sIgE to Hymenoptera venoms as well as sIgE to rapeseed as a marker of cross-reactive carbohydrate determinants were measured. In addition, an atopy score was determined for each patient. We looked for a possible association between tIgE and the presence of sIgE in subjects with a negative history of large local or systemic reactions to insect stings. RESULTS: Fifteen of 65 subjects (23.1%) with low levels of tIgE (<50 kU/l) had sIgE for bee or wasp venom, and 23 of 47 subjects (48.9%) with a tIgE from 50 to 250 kU/l showed sIgE. The highest rate of asymptomatic sensitization (22 of 33; 66.7%) was found in patients with tIgE levels higher than 250 kU/l. Median sIgE was approximately 4.8 times higher in subjects with tIgE levels above 250 kU/l than in those with tIgE levels <50 kU/l. Interestingly, a significant difference in median tIgE was recorded between individuals with and without sIgE to rapeseed [776.5 kU/l (25, 75% percentiles: 252.5, 2,000.0) vs. 50.5 kU/l (20.1, 172.0), respectively; p < 0001]. CONCLUSION: Specific antibodies are frequently seen in individuals with high tIgE, but appear to be largely irrelevant in clinical terms. This might lead to misdiagnosis in persons with an inconclusive sting history.
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Venenos de Abeja/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Venenos de Avispas/inmunología , Adulto , Animales , Especificidad de Anticuerpos/inmunología , Venenos de Artrópodos/inmunología , Brassica rapa/inmunología , Reacciones Cruzadas/inmunología , Femenino , Humanos , Himenópteros/inmunología , Hipersensibilidad/diagnóstico , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Radiodermatitis/etiología , Dermatosis del Cuero Cabelludo/etiología , Enfermedades Cutáneas Vesiculoampollosas/etiología , Quemadura Solar/etiología , Luz Solar/efectos adversos , Administración Cutánea , Adulto , Humanos , Iminas , Masculino , Piridinas/administración & dosificación , Radiodermatitis/clasificación , Radiodermatitis/diagnóstico , Dermatosis del Cuero Cabelludo/clasificación , Dermatosis del Cuero Cabelludo/diagnóstico , Enfermedades Cutáneas Vesiculoampollosas/clasificación , Enfermedades Cutáneas Vesiculoampollosas/diagnóstico , Quemadura Solar/diagnóstico , Resultado del TratamientoRESUMEN
Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.