RESUMEN
The successful treatment of oncological malignancies which results in long-term disease control or the complete eradication of cancerous cells necessitates the onset of adaptive immune responses targeting tumor-specific antigens. Such desirable anticancer immunity can be triggered via the induction of immunogenic cell death (ICD) of cancer cells, thus converting malignant cells into an in situ vaccine that elicits T cell mediated adaptive immune responses and establishes durable immunological memory. The exploration of ICD for cancer treatment has been subject to extensive research. However, functional heterogeneity among ICD activating therapies in many cases requires specific co-medications to achieve full-blown efficacy. Here, we described the hallmarks of ICD and classify ICD activators into three distinct functional categories namely, according to their mode of action: (i) ICD inducers, which increase the immunogenicity of malignant cells, (ii) ICD sensitizers, which prime cellular circuitries for ICD induction by conventional cytotoxic agents, and (iii) ICD enhancers, which improve the perception of ICD signals by antigen presenting dendritic cells. Altogether, ICD induction, sensitization and enhancement offer the possibility to convert well-established conventional anticancer therapies into immunotherapeutic approaches that activate T cell-mediated anticancer immunity.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/patología , Antineoplásicos/farmacología , Muerte Celular , Antígenos de Neoplasias , Linfocitos TRESUMEN
IMPORTANCE: Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that replicates well in mosquito, bird, and mammalian cells. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in the serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and poses a threat to mammalian health. Thus, understanding the pathogenic mechanism of DTMUV is crucial for identifying potential antiviral targets. In this study, we discovered that NS3 can induce the mitochondria-mediated apoptotic pathway through the PERK/PKR pathway; it can also interact with voltage-dependent anion channel 2 to induce apoptosis. Our findings provide a theoretical basis for understanding the pathogenic mechanism of DTMUV infection and identifying potential antiviral targets and may also serve as a reference for exploring the pathogenesis of other flaviviruses.
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Apoptosis , Patos , Infecciones por Flavivirus , Flavivirus , Especificidad del Huésped , Animales , Humanos , Antivirales/farmacología , Patos/virología , eIF-2 Quinasa/metabolismo , Flavivirus/enzimología , Flavivirus/patogenicidad , Infecciones por Flavivirus/diagnóstico , Infecciones por Flavivirus/inmunología , Infecciones por Flavivirus/transmisión , Infecciones por Flavivirus/virología , Mitocondrias/metabolismo , Terapia Molecular Dirigida/tendencias , Zoonosis Virales/diagnóstico , Zoonosis Virales/inmunología , Zoonosis Virales/transmisión , Zoonosis Virales/virología , Canal Aniónico 2 Dependiente del Voltaje/metabolismoRESUMEN
Duck Tembusu virus (DTMUV), a member of the family Flaviviridae and an economically important pathogen with a broad host range, leads to markedly decreased egg production. However, the molecular mechanism underlying the host-DTMUV interaction remains unclear. Here, we performed high-throughput RNA sequencing (RNA-Seq) to study the dynamic changes in host gene expression at 12, 24, 36, 48 and 60 h post-infection (hpi) in duck embryo fibroblasts (DEF) infected with DTMUV. A total of 3129 differentially expressed genes (DEG) were identified after DTMUV infection. Gene Ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that these DEG were associated with multiple biological functions, including signal transduction, host immunity, virus infection, cell apoptosis, cell proliferation, and pathogenicity-related and metabolic process signaling pathways. This study analyzed viral infection and host immunity induced by DTMUV infection from a novel perspective, and the results provide valuable information regarding the mechanisms underlying host-DTMUV interactions, which will prove useful for the future development of antiviral drugs or vaccines for poultry, thus benefiting the entire poultry industry.
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Infecciones por Flavivirus , Flavivirus , Enfermedades de las Aves de Corral , Animales , Patos , Fibroblastos , Flavivirus/fisiología , Infecciones por Flavivirus/veterinaria , Expresión Génica , Análisis de Secuencia de ARN/veterinariaRESUMEN
Duck Tembusu virus (DTMUV) is a pathogenic flavivirus that has caused enormous economic losses in Southeast Asia. Our previous study showed that DTMUV could induce duck embryo fibroblast (DEF) apoptosis, but the specific mechanism was not clear. In this study, we confirmed that DTMUV could induce the apoptosis of DEFs by DAPI staining and TUNEL staining. Furthermore, we found that the expression levels of cleaved-caspase-3/7/8/9 were significantly upregulated after DTMUV infection. After treatment of cells with an inhibitor of caspase-8 or caspase-9, DTMUV-induced apoptosis rates were significantly decreased, indicating that the caspase-8-mediated death receptor apoptotic pathway and caspase-9-mediated mitochondrial apoptotic pathway were involved in DTMUV-induced apoptosis. Moreover, we found that DTMUV infection not only caused the release of mitochondrial cytochrome C (Cyt C) and the downregulation of the apoptosis-inhibiting protein Bcl-2 but also reduced the mitochondrial membrane potential (MMP) and the accumulation of intracellular reactive oxygen species (ROS). Key genes in the mitochondrial apoptotic pathway and death receptor apoptotic pathway were upregulated to varying degrees, indicating the activation of the mitochondrial apoptosis pathway and death receptor apoptosis pathway. In conclusion, this study clarifies the molecular mechanism of DTMUV-induced apoptosis and provides a theoretical basis for revealing the pathogenic mechanism of DTMUV infection.
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Infecciones por Flavivirus , Flavivirus , Enfermedades de las Aves de Corral , Animales , Apoptosis , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Patos/metabolismo , Fibroblastos , Flavivirus/fisiología , Infecciones por Flavivirus/veterinaria , Receptores de Muerte Celular/metabolismoRESUMEN
The changes of metabolite profiles in preterm birth have been demonstrated using newborn screening data. However, little is known about the holistic metabolic model in preterm neonates. The aim was to investigate the holistic metabolic model in preterm neonates. All metabolite values were obtained from a cohort data of routine newborn screening. A total of 261 758 newborns were recruited and randomly divided into a training subset and a testing subset. Using the training subset, 949 variates were considered to establish a logistic regression model for identifying preterm birth (<37 weeks) from term birth (≥37 weeks). Sventy-two variates (age at collection, TSH, 17α-OHP, proline, tyrosine, C16:1-OH, C18:2, and 65 ratios) entered into the final metabolic model for identifying preterm birth from term birth. Among the variates entering into the final model of PTB [Leucine+Isoleucine+Proline-OH)/Valine (OR=38.36], (C3DC+C4-OH)/C12 (OR=15.58), Valine/C5 (OR=6.32), [Leucine+isoleucine+Proline-OH)/Ornithine (OR=2.509)], and Proline/C18:1 (OR=2.465) have the top five OR values, and [Leucine+Isoleucine+Proline-OH)/C5 (OR=0.05)], [Leucine+Isoleucine+Proline-OH)/Phenylalanine (OR=0.214)], proline/valine (OR=0.230), C16/C18 (OR=0.259), and Alanine/free carnitine (OR=0.279) have the five lowest OR values. The final metabolic model had a capacity of identifying preterm infants with >80% accuracy in both the training and testing subsets. When identifying neonates ≤32 weeks from those >32 weeks, it had a robust performance with nearly 95% accuracy in both subsets. In summary, we have established an excellent metabolic model in preterm neonates. These findings could provide new insights for more efficient nutrient supplements and etiology of preterm birth.
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Recien Nacido Prematuro/metabolismo , Modelos Biológicos , Espectrometría de Masas en Tándem , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Modelos Logísticos , Masculino , Metaboloma , Análisis Multivariante , Nacimiento Prematuro/diagnóstico , Nacimiento Prematuro/metabolismo , Curva ROCRESUMEN
Mammalian interferon-induced protein with tetratricopeptide repeats family proteins (IFITs) play important roles in host innate immune response to viruses. Recently, studies have shown that IFIT from poultry also plays a crucial part in antiviral function. This study first reports the regulation of duck Tembusu virus (DTMUV) replication by IFIT5 and the effect of duck IFIT5 (duIFIT5) on the innate immune response after DTMUV infection. Firstly, duIFIT5 was obviously increased in duck embryo fibroblast cells (DEFs) infected with DTMUV. Compared to the negative control, we found that in the duIFIT5-overexpressing group, the DTMUV titer at 24 h post infection (hpi) was significantly reduced, but the viral titer was strikingly increased at 48 hpi. Moreover, overexpression of duIFIT5 could significantly inhibit IFN-ß transcription and IFN-ß promoter activation at indicated time points after DTMUV infection. Further, in DTMUV-infected or poly(I:C)-stimulated DEFs, overexpression of duIFIT5 also significantly inhibited the activation of NF-κB and IRF7 promoters, as well as the activation of downstream IFN induced the interferon-stimulated response element (ISRE) promoter. Meanwhile, the transcription level of antiviral protein Mx, but not OASL, was obviously decreased at various time points. The opposite results were obtained by knockdown of duIFIT5 in DTMUV-infected or poly(I:C)-stimulated DEFs. Compared to the negative control, knockdown of duIFIT5 promoted DTMUV titer and DTMUV envelope (E) protein expression at 24 hpi, but DTMUV titer and E protein expression was markedly decreased at 48 hpi. Additionally, the promoters of IFN-ß, NF-κB, IRF7 and ISRE were significantly activated in the duIFIT5 knockdown group. Collectively, duIFIT5 differentially regulates DTMUV replication and inhibits virus-triggered innate immune response.
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Flavivirus/inmunología , Inmunidad Innata/inmunología , Proteínas de Neoplasias/inmunología , Replicación Viral/inmunología , Animales , Antivirales/inmunología , Patos , Fibroblastos/inmunología , Interferón beta/inmunología , FN-kappa B/inmunología , Poli I-C/inmunología , Regiones Promotoras Genéticas/inmunología , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: To explore the molecular basis for a Chinese family affected with neurofibromatosis type I. METHODS: Peripheral blood samples were collected from the proband and his parents. Potential mutations of NF1 gene were screened by PCR and Sanger sequencing. Pathogenicity of candidate mutations was analyzed using Polyphen-2 and Provean software. RESULTS: Two mutations of the NF1 gene, including c.702G>A (synonymous mutation) and c.1733T>G (missense mutation), were discovered in the proband. Neither mutation was found in his parents and 50 healthy controls. Bioinformatics analysis indicated that the c.1733T>G mutation (p.Leu578Arg) was probably damaging. The affected codon L578 is highly conserved across various species. CONCLUSION: The c.1733T>C mutation of the NF1 gene probably underlies the neurofibromatosis type I in this family.
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Genes de Neurofibromatosis 1 , Neurofibromatosis 1 , Neurofibromina 1/genética , Pueblo Asiatico , Humanos , Mutación , Neurofibromatosis 1/genética , LinajeRESUMEN
BACKGROUND: The pathogenesis of allergic asthma is primarily characterized by abnormality in the immunoglobulin E (IgE) pathway, suggesting a possible role for follicular T-helper cells (Tfh) in the genesis of excessive IgE accumulation. The blood chemokine (C-X-C motif) receptor 5 (CXCR5)+CD4+ T cells, known as circulating Tfh, share common functional characteristics with Tfh cells from germinal centers. There are three subsets of circulating Tfh cells: Tfh1 (CXCR3+CC chemokine receptor [CCR] 6), Tfh2 (CXCR3CCR6) and Tfh17 (CXCR3CCR6+). However, data on circulating Tfh cell subsets distribution in patients with asthma are not available. OBJECTIVE: To investigate the circulating Tfh cell subsets distribution in patients with asthma and to assess the relationship between Tfh cell subsets distribution and the serum IgE level. METHODS: Thirty patients with severe allergic asthma and 30 age- and sex-matched healthy controls were enrolled in this study. The percentages and phenotypic assays of circulating Tfh cell subsets were assessed by flow cytometry. The total IgE levels were also measured. The correlation between the percentage of circulating Tfh cell subsets and the levels of serum total IgE was analyzed. RESULTS: Our results showed polarization of Tfh2 cells within circulating Tfh cell subsets in the patients with asthma. Phenotypic assays showed that activated Tfh2 subtypes displayed the features of Tfh cells, including invariably coexpressed programmed cell death 1 (PD-1), and inducible costimulator (ICOS). Furthermore, not only the frequency of Tfh2 cells but also the ratio (%Tfh2/%Tfh1) positively correlated with the total IgE level in the blood. CONCLUSION: Results of our data described an altered circulating Tfh subset distribution, which implied that this cell subset might play an important role in the pathogenesis of asthma.
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Asma/sangre , Asma/inmunología , Recuento de Linfocitos , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Antiasmáticos/administración & dosificación , Antígenos de Superficie/metabolismo , Asma/diagnóstico , Asma/tratamiento farmacológico , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Our case series showed that uncomplicated Yarrowia lipolytica fungemia might be treated with catheter removal alone. The Vitek 2 YST identification (ID) card system, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and internal transcribed spacer and 25S nuclear ribosomal DNA (nrDNA) gene sequencing provided reliable identification. All isolates had low MICs to voriconazole, echinocandins, and amphotericin B.
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Antifúngicos/uso terapéutico , Infecciones Relacionadas con Catéteres/diagnóstico , ADN Espaciador Ribosómico/genética , Fungemia/diagnóstico , Fungemia/tratamiento farmacológico , Yarrowia/genética , Adulto , Anciano , Anciano de 80 o más Años , Anfotericina B/farmacología , Secuencia de Bases , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Infecciones Relacionadas con Catéteres/microbiología , Cateterismo Venoso Central/efectos adversos , Cateterismo Periférico/efectos adversos , Preescolar , Equinocandinas/farmacología , Femenino , Fungemia/microbiología , Hospitalización , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Datos de Secuencia Molecular , Estudios Prospectivos , Análisis de Secuencia de ADN , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Voriconazol/farmacología , Yarrowia/efectos de los fármacosRESUMEN
BACKGROUND: Bronchial asthma is a chronic airway inflammatory disease primarily characterized by an abnormality in the IgE pathway. Follicular helper T (Tfh) cells are the specialized subset indispensible for providing cognate help to B cells during formation of germinal centers. The more recent work presents clear evidence that human blood CD4+ CXCR5+ T cells, circulating Tfh (cTfh) cells, are counterparts of Tfh cells in germinal centers. METHODS: 11 patients with mild asthma, 15 severe asthma patients, and 20 healthy controls were enrolled in this study. The percentages of cTfh cells were assessed by flow cytometry. The correlation between the percentage of cTfh cells and the level of serum total IgE was also analyzed. Additionally, the serum level of IL-21 was quantified by ELISA. Expression of Bcl-6 mRNA and IL-21 mRNA were assayed by real-time polymerase chain reaction. RESULTS: The frequency of the cTfh cells was significantly higher in severe asthma than in mild asthma patients and in healthy individuals and positively correlated with total IgE in blood. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in asthma patients was increased. CONCLUSIONS: Our findings provide evidence of increased frequency of cTfh cells in asthma patients, which implies that this cell subset might play an important role in the pathogenesis of asthma.
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Asma/sangre , Asma/inmunología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Análisis de Varianza , Proteínas de Unión al ADN/sangre , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina E/sangre , Interleucinas/sangre , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores CXCR5/inmunología , Adulto JovenRESUMEN
Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.
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Anorexia , Inhibidor de la Unión a Diazepam , Animales , Inhibidor de la Unión a Diazepam/metabolismo , Anorexia/tratamiento farmacológico , Anorexia/metabolismo , Humanos , Ratones Transgénicos , Ratones , Anorexia Nerviosa/metabolismo , Anorexia Nerviosa/tratamiento farmacológico , Lipocalina 2/metabolismo , Lipocalina 2/sangre , Hipotálamo/metabolismo , Masculino , Femenino , Ratones Endogámicos C57BL , Restricción Física , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacosRESUMEN
Gardenia jasminoides fruits are extensively grown worldwide, with a large harvest, and its major medicinal ingredients are geniposide and crocins. Research on their accumulation and biosynthsis-related enzymes is rare. In this study, the accumulation of geniposide and crocin of G. jasminoides fruits at different developmental stages were clarified by HPLC. The highest cumulative amount of geniposide was 2.035% during the unripe-fruit period, and the highest content of crocin was 1.098% during the mature-fruit period. Furthermore, transcriptome sequencing was performed. A total of 50 unigenes encoding 4 key enzymes related in geniposide biosynthsis pathways were screened, and 41 unigenes encoding 7 key enzymes in the pathways of crocin were elucidated. It was found that the expression levels of differentially expressed genes of DN67890_c0_g1_i2-encoding GGPS, which is highly related to geniposide biosynthesis, and DN81253_c0_g1_i1-encoding lcyB, DN79477_c0_g1_i2-encoding lcyE, and DN84975_c1_g7_i11-encoding CCD, which are highly related to crocin biosynthesis, were consistent with the accumulation of geniposide and crocin content, respectively. The qRT-PCR results showed that the trends of relative expression were consistent with transcribed genes. This study provides insights for understanding the geniposide and crocin accumulation and biosynthsis during fruit development in G. jasminoides.
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Toll-like receptor 3 (TLR3) agonists such as polyinosinic:polycytidylic acid (poly(I:C)) have immunostimulatory effects that can be taken advantage of to induce anticancer immune responses in preclinical models. In addition, poly(I:C) has been introduced into clinical trials to demonstrate its efficacy as an adjuvant and to enhance the immunogenicity of locally injected tumors, thus reverting resistance to PD-L1 blockade in melanoma patients. Here, we report the pharmacokinetic, pharmacodynamic, mechanistic and toxicological profile of a novel TLR3 agonist, TL-532, a chemically synthesized double-stranded RNA that is composed by blocks of poly(I:C) and poly(A:U) (polyadenylic - polyuridylic acid). In preclinical models, we show that TL-532 is bioavailable after parenteral injection, has an acceptable toxicological profile, and stimulates the production of multiple chemokines and interleukins that constitute pharmacodynamic markers of its immunostimulatory action. When given at a high dose, TL-532 monotherapy reduced the growth of bladder cancers growing on mice. In addition, in immunodeficient mice lacking formylpeptide receptor-1 (FPR1), TL-532 was able to restore the response of orthotopic subcutaneous fibrosarcoma to immunogenic chemotherapy. Altogether, these findings may encourage further development of TL-532 as an immunotherapeutic anticancer agent.
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Melanoma , Receptor Toll-Like 3 , Animales , Ratones , Adyuvantes Inmunológicos , Melanoma/tratamiento farmacológico , Poli I-C/farmacologíaRESUMEN
Invasive diseases caused by the globally distributed commensal yeast Candida tropicalis are associated with mortality rates of greater than 50%. Notable increases of azole resistance have been observed in this species, particularly within Asia-Pacific regions. Here, we carried out a genetic population study on 1571 global C. tropicalis isolates using multilocus sequence typing (MLST). In addition, whole-genome sequencing (WGS) analysis was conducted on 629 of these strains, comprising 448 clinical invasive strains obtained in this study and 181 genomes sourced from public databases. We found that MLST clade 4 is the predominant azole-resistant clone. WGS analyses demonstrated that dramatically increasing rates of azole resistance are associated with a rapid expansion of cluster AZR, a sublineage of clade 4. Cluster AZR isolates exhibited a distinct high-level azole resistance, which was induced by tandem duplications of the ERG11A395T gene allele. Ty3/gypsy-like retrotransposons were found to be highly enriched in this population. The alarming expansion of C. tropicalis cluster AZR population underscores the urgent need for strategies against growing threats of antifungal resistance.
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Antifúngicos , Azoles , Azoles/farmacología , Antifúngicos/farmacología , Candida tropicalis/genética , Tipificación de Secuencias Multilocus , Duplicación de Gen , Farmacorresistencia Fúngica/genética , Pruebas de Sensibilidad MicrobianaRESUMEN
The tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) is a key signaling molecule in the retinoic acid-inducible gene I (RIG-I) signaling pathway and plays an important role in host innate immune regulation. The function of TRAF3 has been extensively studied in mammals, however, the role of TRAF3 in ducks remains unclear. In order to reveal the function of duck TRAF3 (duTRAF3) in the innate immune response induced by virus infection, the TRAF3 homologue of mallard (Anas platyrhynchos) has been cloned and the function of duTRAF3 is investigated in this study. We sequenced duTRAF3 and found that the open reading frame (ORF) region of duTRAF3 is 1704 bp long and encodes 567 amino acids (aa), which has a similar functional domain to the mammalian gene. Analysis of tissue distribution of duTRAF3 in 7-day-old ducks showed that the expression of duTRAF3 was highest in harderian gland, followed by heart and lung. Subsequently, duck Tembusu virus (DTMUV) has been shown to enhance duTRAF3 expression, and overexpression of duTRAF3 inhibits DTMUV replication in a dose-dependent manner. In addition, duTRAF3 activates the transcriptional activity of IFN-α and its downstream interferon-stimulating genes (ISGs) induced after DTMUV infection. In this process, DTMUV non-structural (NS) protein 5 resists this innate immune process by interacting with TRAF3 and inhibiting TRAF3 expression. These data support the conclusion that duTRAF3 is an antiviral protein that plays a key role in the defense against DTMUV invasion. These results lay a theoretical foundation for developing new anti-DTMUV strategies.
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Infecciones por Flavivirus , Flavivirus , Interferón Tipo I , Enfermedades de las Aves de Corral , Animales , Patos , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/metabolismo , Infecciones por Flavivirus/veterinaria , Flavivirus/genética , Inmunidad Innata/genética , Transducción de Señal , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , MamíferosRESUMEN
Formyl peptide receptor-1 (FPR1) is a pattern recognition receptor that is mostly expressed by myeloid cells. In patients with colorectal cancer (CRC), a loss-of-function polymorphism (rs867228) in the gene coding for FPR1 has been associated with reduced responses to chemotherapy or chemoradiotherapy. Moreover, rs867228 is associated with accelerated esophageal and colorectal carcinogenesis. Here, we show that dendritic cells from Fpr1-/- mice exhibit reduced migration in response to chemotherapy-treated CRC cells. Moreover, Fpr1-/- mice are particularly susceptible to chronic ulcerative colitis and colorectal oncogenesis induced by the mutagen azoxymethane followed by oral dextran sodium sulfate, a detergent that induces colitis. These experiments were performed after initial co-housing of Fpr1-/- mice and wild-type controls, precluding major Fpr1-driven differences in the microbiota. Pharmacological inhibition of Fpr1 by cyclosporin H also tended to increase intestinal oncogenesis in mice bearing the ApcMin mutation, and this effect was reversed by the anti-inflammatory drug sulindac. We conclude that defective FPR1 signaling favors intestinal tumorigenesis through the modulation of the innate inflammatory/immune response.
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Colitis , Neoplasias Colorrectales , Animales , Ratones , Carcinogénesis/genética , Colitis/inducido químicamente , Colitis/genética , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Receptores de Formil Péptido/genética , Transducción de SeñalRESUMEN
We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance. SIGNIFICANCE: BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.
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Antineoplásicos , Neoplasias , Humanos , Animales , Ratones , Células Dendríticas , Receptor de Muerte Celular Programada 1 , Monitorización Inmunológica , Ratones Noqueados , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
Human cytomegalovirus (HCMV) is a well-studied ß-herpesvirus virus, which adopts a variety of strategies to evade immune surveillance. It has been reported that in HCMV-infected cells, classical major histocompatibility (MHC) class I molecules are down-regulated, but the MHC class Ib molecule human leukocyte antigen (HLA)-E is normally expressed or even overexpressed on the cell surface. HLA-E has been first described to interact with CD94/NKG2 receptors expressed mainly on the surface of natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. The engagement of CD94/NKG2A with HLA-E, with a signal peptide of the HCMV glycoprotein UL40, usually induces inhibitory signals. However, HLA-E also serves as a ligand for the TCR expressed by αßCD8(+) T cells. Recognition of peptides presented by HLA-E may result in CD8(+) effector T-cell activation. These findings will help to understand more on both pathogenic and protective roles of HLA-E in HCMV infection. In this review, we discussed recent studies about the roles of HLA-E in HCMV infection.
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Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Células Asesinas Naturales/inmunología , Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/virología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Modelos Inmunológicos , Subfamília D de Receptores Similares a Lectina de las Células NK/inmunología , Subfamília D de Receptores Similares a Lectina de las Células NK/metabolismo , Unión Proteica , Señales de Clasificación de Proteína , Proteínas Virales/inmunología , Proteínas Virales/metabolismo , Antígenos HLA-ERESUMEN
In the early 2000s, caspase-1, an important molecule that has been shown to be involved in the regulation of inflammation, cell survival and diseases, was given a new function: regulating a new mode of cell death that was later defined as pyroptosis. Since then, the inflammasome, the inflammatory caspases (caspase-4/5/11) and their substrate gasdermins (gasdermin A, B, C, D, E and DFNB59) has also been reported to be involved in the pyroptotic pathway, and this pathway is closely related to the development of various diseases. In addition, important apoptotic effectors caspase-3/8 and granzymes have also been reported to b involved in the induction of pyroptosis. In our article, we summarize findings that help define the roles of inflammasomes, inflammatory caspases, gasdermins, and other mediators of pyroptosis, and how they determine cell fate and regulate disease progression.