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Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.
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Histiocitosis de Células de Langerhans , Humanos , Histiocitosis de Células de Langerhans/tratamiento farmacológicoRESUMEN
The IL-36 cytokines are known to play various roles in mediating the immune response to infection in a tissue- and pathogen-dependent manner. The present study seeks to investigate the role of IL-36R signaling in C57BL/6 mouse corneas in response to Pseudomonas aeruginosa infection. IL-36α-/-, IL-36γ-/-, and IL-36R-/- mice had significantly more severe keratitis than wild-type mice. At six hours postinfection, IL-36α pretreatment augmented P. aeruginosa-induced expression of IL-1Ra, IL-36γ, LCN2, and S100A8/A9. At one day postinfection, exogenous IL-36α suppressed, whereas IL-36α deficiency promoted, the expression of IL-1ß. At three days postinfection, exogenous IL-36α suppressed Th1 but promoted Th2 immune response. IL-36α stimulated the infiltration of IL-22-expressing immune cells, and IL-22 neutralization resulted in more severe keratitis. IL-36α alone stimulated dendritic cell infiltration in B6 mouse corneas. Taken together, our study suggests that IL-36R signaling plays a protective role in the pathogenesis of P. aeruginosa keratitis by promoting the innate immune defense, Th2, and/or Th22/IL-22 immune responses. Exogenous IL-36α might be a potential therapy for improving the outcome of P. aeruginosa keratitis.
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Córnea/inmunología , Interleucina-1/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Animales , Interleucina-1/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Flexible control of light absorption within the lithography-free nanostructure is crucial for many polarization-dependent optical devices. Herein, we demonstrated that the lithography-free tunable absorber (LTA) can be realized by using two one-dimensional (1D) photonic crystals (PCs) consisting of an α-MoO3 layer at visible region. The two 1D PCs have different bulk band properties, and the topological interface state-induced light absorption enhancement of α-MoO3 can be realized as the α-MoO3 thin film is inserted at the interface between the two 1D PCs. The resonant cavity model is proposed to evaluate the anisotropic absorption performances of the LTA, and the results are in good agreement with those of the transfer matrix method (TMM). The absorption efficiency of the LTA can be tailored by the number of the period of the two PCs, and the larger peak absorption is the direct consequence of the larger field enhancement factor (FEF) within the α-MoO3 layer. In addition, near-perfect absorption can be achieved as the LTA is operated at the over-coupled resonance. By varying the polarization angle, the absorption channels can be selected and the reflection response can be effectively modulated due to the excellent in-plane anisotropy of α-MoO3.
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As the most potent professional antigen presenting cells, dendritic cells (DCs) have the ability to activate both naive CD4 and CD8 T cells. Recognized for their exceptional ability to cross-present exogenous antigens to prime naive antigen-specific CD8 T cells, DCs play a critical role in generating CD8 T cell immunity, as well as mediating CD8 T cell tolerance to tumor antigens. Despite the ability to potentiate host CD8 T cell-mediated anti-tumor immunity, current DC-based cancer vaccines have not yet achieved the promised success clinically with the exception of FDA-approved Provenge. Interestingly, recent studies have shown that type 1 conventional DCs (cDC1s) play a critical role in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies including immune checkpoint blockade (ICB). Together with promising clinical results in neoantigen-based cancer vaccines, there is a great need for DC-based vaccines to be further developed and refined either as monotherapies or in combination with other immunotherapies. In this review, we will present a brief review of DC development and function, discuss recent progress, and provide a perspective on future directions to realize the promising potential of DC-based cancer vaccines.
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Vacunas contra el Cáncer , Neoplasias , Humanos , Presentación de Antígeno , Antígenos de Neoplasias , Linfocitos T CD8-positivos , Células DendríticasRESUMEN
Invariant natural killer T cells (iNKT) are a prevalent population of innate-like T cells in mice, but quite rare in humans that are critical for regulation of the innate and adaptive immune responses during antimicrobial immunity, tumor rejection, and inflammatory diseases. Multiple transcription factors and signaling molecules that contribute to iNKT cell selection and functional differentiation have been identified. However, the full molecular network responsible for regulating and maintaining iNKT populations remains unclear. MicroRNAs (miRNAs) are an abundant class of evolutionarily conserved, small, non-coding RNAs that regulate gene expression post-transcriptionally. Previous reports uncovered the important roles of miRNAs in iNKT cell development and function using Dicer mutant mice. In this review, we discuss the emerging roles of individual miRNAs in iNKT cells reported by our group and other groups, including miR-150, miR-155, miR-181, let-7, miR-17 ~ 92 cluster, and miR-183-96-182 cluster. It is likely that iNKT cell development, differentiation, homeostasis, and functions are orchestrated through a multilayered network comprising interactions among master transcription factors, signaling molecules, and dynamically expressed miRNAs. We provide a comprehensive view of the molecular mechanisms underlying iNKT cell differentiation and function controlled by dynamically expressed miRNAs.
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MicroARNs/genética , Células T Asesinas Naturales/fisiología , Animales , Diferenciación Celular/genética , Expresión Génica/genética , Humanos , Transducción de Señal/genéticaRESUMEN
Epidermal resident γδ T cells, or dendritic epidermal T cells (DETCs) in mice, are a unique and conserved population of γδ T cells enriched in the epidermis, where they serve as the regulators of immune responses and sense skin injury. Despite the great advances in the understanding of the development, homeostasis, and function of DETCs in the past decades, the origin and the underlying molecular mechanisms remain elusive. Here, we reviewed the recent research progress on DETCs, including their origin and homeostasis in the skin, especially at transcriptional and epigenetic levels, and discuss the involvement of DETCs in skin diseases.
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Epidermis/inmunología , Linfocitos Intraepiteliales/inmunología , Enfermedades de la Piel/inmunología , Piel/inmunología , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Epidermis/metabolismo , Epigénesis Genética , Humanos , Linfocitos Intraepiteliales/citología , Linfocitos Intraepiteliales/metabolismo , Ratones , Piel/citología , Piel/metabolismo , Enfermedades de la Piel/genética , Timo/citología , Timo/inmunología , Timo/metabolismo , Saco Vitelino/citología , Saco Vitelino/inmunología , Saco Vitelino/metabolismoRESUMEN
Ultrabroadband absorbers are vital for applications such as solar energy harvesting and integrated optoelectronic devices. Herein, we design, fabricate and characterize a novel ultrabroadband and ultrathin absorber based on the encapsulated T-shaped metasurface (ETM). The ETM consists of a 20â nm Cr film and a Cr substrate sandwiched by the T-shaped polymethyl methacrylate (PMMA) arrays. The Cr film provides a robust absorptive surface with improved impedance matching, and ultrabroadband absorption can be achieved via the excitation of the localized surface plasmon (LSP) of this ultrathin film. The average absorption of simulated and experimental results of the ETM in the visible range of 400-800â nm for the TM (TE) polarization are 96.4% (96.3%) and 90.6% (89.4%), respectively. Three-dimensional (3D) power dissipation density distributions of the proposed structure have been investigated, which indicates that the synergistic absorption effect of different parts of the T-shaped ultrathin Cr film contributes to the major absorption enhancement. The absorption of the ETM is very robust to the changes of geometrical parameters and the symmetry of the structure, and it can be maintained almost the same even if T-shaped profiles are changed to L-shaped profiles. Moreover, the absorption performance of the ETM exhibits polarization-insensitive and wide-angle features, which has advantages for many potential applications.
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The development, differentiation and function of invariant NKT (iNKT) cells require a well-defined set of transcription factors, but how these factors are integrated to each other and the detailed signaling networks remain poorly understood. Using a Dicer-deletion mouse model, our previous studies have demonstrated the critical involvement of microRNAs (miRNAs) in iNKT cell development and function, but the role played by individual miRNAs in iNKT cell development and function is still not clear. In this study, we show the dynamic changes of miRNA 183 cluster (miR-183C) expression during iNKT cell development. Mice with miR-183C deletion showed a defective iNKT cell development, sublineage differentiation, and cytokine secretion function. miRNA target identification assays indicate the involvement of multiple target molecules. Our study not only confirmed the role of miR-183C in iNKT cell development and function but also demonstrated that miR-183C achieved the regulation of iNKT cells through integrated targeting of multiple signaling molecules and pathways.
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Diferenciación Celular/genética , MicroARNs/genética , Familia de Multigenes , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Animales , Expresión Génica , Regulación de la Expresión Génica , Homeostasis , Ratones , Células T Asesinas Naturales/citología , Interferencia de ARNAsunto(s)
Carcinoma Basocelular , Carcinoma de Células Escamosas , Queratoacantoma , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Queratoacantoma/cirugía , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Cirugía de Mohs , Carcinoma Basocelular/patología , Recurrencia Local de Neoplasia/cirugíaRESUMEN
Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1ß) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1ß protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1ß activity, resulting in renal tubular cell apoptosis and nephrotoxicity.
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Antineoplásicos/toxicidad , Cisplatino/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Factor Nuclear 1-beta del Hepatocito/genética , Riñón/efectos de los fármacos , MicroARNs/genética , Animales , Apoptosis/efectos de los fármacos , Riñón/metabolismo , Ratones , Ratones Noqueados , Ribonucleasa III/genéticaRESUMEN
The urate oxidase (Uox) gene encodes uricase that in the rodent liver degrades uric acid into allantoin, forming an obstacle for establishing stable mouse models of hyperuricemia. The loss of uricase in humans during primate evolution causes their vulnerability to hyperuricemia. Thus, we generated a Uox-knockout mouse model on a pure C57BL/6J background using the transcription activator-like effector nuclease (TALEN) technique. These Uox-knockout mice spontaneously developed hyperuricemia (over 420 µmol/l) with about 40% survival up to 62 weeks. Renal dysfunction (elevated serum creatinine and blood urea nitrogen) and glomerular/tubular lesions were observed in these Uox-knockout mice. Male Uox-knockout mice developed glycol-metabolic disorders associated with compromised insulin secretion and elevated vulnerability to streptozotocin-induced diabetes, whereas female mice developed hypertension accompanied by aberrant lipo-metabolism. Urate-lowering drugs reduced serum uric acid and improved hyperuricemia-induced disorders. Thus, uricase knockout provides a suitable mouse model to investigate hyperuricemia and associated disorders mimicking the human condition, suggesting that hyperuricemia has a causal role in the development of metabolic disorders and hypertension.
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Hiperuricemia/enzimología , Riñón/metabolismo , Hígado/enzimología , Urato Oxidasa/deficiencia , Ácido Úrico/sangre , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Presión Sanguínea , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Dislipidemias/sangre , Dislipidemias/enzimología , Dislipidemias/genética , Femenino , Predisposición Genética a la Enfermedad , Supresores de la Gota/farmacología , Hipertensión/enzimología , Hipertensión/genética , Hipertensión/fisiopatología , Hiperuricemia/sangre , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/genética , Insulina/sangre , Riñón/patología , Riñón/fisiopatología , Lípidos/sangre , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Factores de Tiempo , Urato Oxidasa/genéticaRESUMEN
In this study, we developed a multifunctional device based on SnO2@rGO-coated fibers utilizing plasma treatment, dip coating, and microwave irradiation in sequence, and finally realized highly sensitive human motion monitoring, relatively good ethanol detection, and an obvious photo response. Moreover, the high level of comfort and compactness derived from highly elastic and comfortable fabrics contributes to the long-term availability and test accuracy. As an attempt at multifunctional integration of smart clothing, this work provides an attractive and relatively practical research direction.
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Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of α-galactosylceramide (α-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent α-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of α-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator-activated receptor (PPAR)γ activation, through rosiglitazone treatment, reduced the rate of α-GalCer-induced late PTB and improved neonatal survival. Administration of α-GalCer in the third trimester suppressed PPARγ activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of α-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of α-GalCer also upregulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPARγ pathway has potential as a target for prevention of this syndrome.
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Activación de Linfocitos/efectos de los fármacos , Células T Asesinas Naturales/inmunología , PPAR gamma/agonistas , Nacimiento Prematuro/inmunología , Tiazolidinedionas/farmacología , Animales , Citocinas/sangre , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Galactosilceramidas/toxicidad , Humanos , Hipoglucemiantes/farmacología , Inmunofenotipificación , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Embarazo , Reacción en Cadena en Tiempo Real de la Polimerasa , RosiglitazonaRESUMEN
MicroRNAs (miRNAs) play very important roles in the control of immune cell and keratinocyte development and function and are implicated in skin inflammatory diseases, including psoriasis. miRNA miR-17-92 was reported to promote the differentiation of Th1 and Th1 cells and to regulate cell proliferation and apoptosis. Here we showed that imiquimod (IMQ) differentially regulates the expression of miR-17-92 cluster in the mouse skin, upregulating miR-17 and miR-19 families and downregulating miR-92. To investigate whether miR-17-92 cluster is functionally involved in the psoriasis, we have generated three mutant mice with specific deletion or overexpression of miR-17-92 cluster in keratinocytes, or with deletion of miR-17-92 cluster in T cells. Interestingly, deletion or overexpression of miR-17-92 cluster in keratinocytes, or deletion of miR-17-92 in T cells did not significantly affect IMQ-induced psoriasis-like dermatitis development in the mutant mice compared with wild-type littermates. Thus, miRNA miR-17-92 cluster may not be a key factor regulating imiqumod-induced psoriasis-like dermatitis.
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MicroARNs/genética , Psoriasis/genética , Aminoquinolinas , Animales , Regulación hacia Abajo , Imiquimod , Queratinocitos , Ratones , Ratones Noqueados , Psoriasis/inducido químicamente , Psoriasis/patología , Linfocitos T , Regulación hacia ArribaRESUMEN
MicroRNAs (miRNAs) are small non-coding RNA molecules, which function in RNA silencing and post-transcriptional regulation of gene expression. Psoriasis is an inflammatory skin disease characterized by the dysfunction of keratinocytes, with the immune dysregulation. We reviewed the recent studies on the roles of miRNAs in psoriasis and showed that miRNAs play key roles in psoriasis, including the regulation of hyperproliferation, cytokine and chemokine production in keratinocyte, as well as mediating immune dysfunction in psoriasis. Furthermore, miRNAs, particularly, circulating miRNAs may serve as novel biomarkers for diagnosis, monitoring therapy response and reflecting the disease severity. Thus, targeting specific miRNAs may be used to develop new therapeutic methods for psoriasis.
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MicroARNs/genética , MicroARNs/inmunología , Psoriasis/genética , Psoriasis/inmunología , Biomarcadores/sangre , Proliferación Celular , Humanos , Inmunidad Celular , Queratinocitos/fisiología , MicroARNs/sangre , Terapia Molecular Dirigida , Psoriasis/sangre , Psoriasis/tratamiento farmacológico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.
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Cirrosis Hepática/metabolismo , Fallo Hepático/metabolismo , MicroARNs/metabolismo , Enfermedad Aguda , Animales , Biomarcadores/metabolismo , Enfermedad Crónica , Femenino , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/genética , Fallo Hepático/diagnóstico , Fallo Hepático/genética , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genéticaRESUMEN
Establishing a definitive diagnosis between benign enchondroma versus low-grade chondrosarcoma presents a potential challenge to both clinicians and pathologists. microRNAs (small non-coding RNAs) have proven to be effective biomarkers for the identification of tumors and tumor progression. We present analysis, both array and quantitative PCR, that shows consistently and substantially increased expression of two microRNAs, miRs-181a and -138, in low-grade chondrosarcomas compared with enchondromas. The data suggest these microRNAs would provide an analytical distinction between the chondrosarcoma and benign neoplasms that can be performed in formalin-fixed paraffin-embedded specimens. Together with recent publications, these data indicate that miRs-181a and -138 also play a role in tumor development and homeostasis and may provide new targets for the development of much needed therapeutic intervention.