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Cardiomyocyte injury is closely related to various myocardial diseases, and S-Allyl-L-cysteine (SAC) has been found to have myocardial protective effects, but its mechanism is currently unclear. Meanwhile, copper also has various physiological functions, and this study found that copper inhibited cell viability in a concentration and time-dependent manner, and was associated with multiple modes of death. Elesclomol plus CuCl2 (ES + Cu) significantly inhibited cell viability, and this effect could only be blocked by copper chelator TTM, indicating that "ES + Cu" induced cuproptosis in cardiomyocytes. SAC reduced the inhibitory effects of high concentration copper and "ES + Cu" on cell viability in a concentration and time-dependent manner, indicating that SAC plays a cardioprotective role under stress. Further mechanism study showed that high concentration of copper significantly induced cardiomyocyte apoptosis and increased the levels of LDH, MDA and ROS, while SAC inhibited the apoptosis and injury of cardiomyocytes induced by copper. "ES + Cu" significantly increased intracellular copper levels and decreased the expression of FDX1, LIAS, Lip-DLST and Lip-DLAT; FDX1 siRNA did not affect the expression of LIAS, but further reduced the expression of Lip-DLST and Lip-DLAT; SAC did not affect the expression of these genes, but enhanced the effect of "ES + Cu" in down-regulating these gene expression and restored intracellular copper levels. In addition, "ES + Cu" reduced ATP production, weakened the activity of mitochondrial complex I and III, inhibited cell viability, and increased the contents of injury markers LDH, MDA, CK-MB and cTnI, while SAC significantly improved mitochondrial function injury and cardiomyocyte injury induced by "ES + Cu". Therefore, SAC can inhibit apoptosis and cuproptosis to play a cardioprotective role.
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Apoptose , Cobre , Cisteína , Miócitos Cardíacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Apoptose/efeitos dos fármacos , Animais , Cisteína/análogos & derivados , Cisteína/farmacologia , Ratos , Sobrevivência Celular/efeitos dos fármacos , Ratos Sprague-Dawley , Células Cultivadas , Espécies Reativas de Oxigênio/metabolismo , Cardiotônicos/farmacologiaRESUMO
ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Robust biomarkers and a complete understanding of CAR T-cell function in the postinfusion phase remain limited. Here, we used a 37-color spectral flow cytometry panel to perform high dimensional single-cell analysis of postinfusion samples in 26 patients treated with CD28 costimulatory domain containing commercial CAR T cells for NHL and focused on computationally gated CD8+ CAR T cells. We found that the presence of postinfusion Programmed cell death protein 1 (PD-1)+ CD8+ CAR T cells at the day 14 time point highly correlated with the ability to achieve complete response (CR) by 6 months. Further analysis identified multiple subtypes of CD8+ PD-1+ CAR T cells, including PD-1+ T cell factor 1 (TCF1)+ stem-like CAR T cells and PD-1+ T-cell immunoglobulin and mucin-domain containing-3 (TIM3)+ effector-like CAR T cells that correlated with improved clinical outcomes such as response and progression-free survival. Additionally, we identified a subset of PD-1+ CD8+ CAR+ T cells with effector-like function that was increased in patients who achieved a CR and was associated with grade 3 or higher immune effector cell-associated neurotoxicity syndrome. Here, we identified robust biomarkers of response to CD28 CAR T cells and highlight the importance of PD-1 positivity in CD8+ CAR T cells after infusion in achieving CR.
Assuntos
Linfócitos T CD8-Positivos , Imunoterapia Adotiva , Linfoma não Hodgkin , Receptor de Morte Celular Programada 1 , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Imunoterapia Adotiva/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Antígenos CD19/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Resultado do TratamentoRESUMO
This study intends to investigate the effects of miR-142-5p encapsulated by serum-derived extracellular vesicles (EVs) on septic acute lung injury (ALI) following remote ischemic preconditioning (RIPC) through a PTEN-involved mechanism. ALI was induced in rats by lipopolysaccharide (LPS) injection, 24 h before which RIPC was performed via the left lower limb. Next, the binding affinity between miR-142-5p and PTEN was identified. EVs were isolated from serum and injected into rats. The morphology of lung tissues, pulmonary edema, and inflammatory cell infiltration into lung tissues were then assessed, and TNF-α and IL-6 levels in serum and lung tissues were measured. The results indicated that RIPC could attenuate ALI in sepsis. miR-142-5p expression was increased in serum, lung tissues, and serum-derived EVs of ALI rats following RIPC. miR-142-5p could target PTEN to activate the PI3K/Akt signaling pathway. miR-142-5p shuttled by serum-derived EVs reduced pulmonary edema, neutrophil infiltration, and TNF-α and IL-6 levels, thus alleviating ALI in LPS-induced septic rats upon RIPC. Collectively, serum-derived EVs-loaded miR-142-5p downregulated PTEN and activated PI3K/Akt to inhibit ALI in sepsis following RIPC, thus highlighting potential therapeutic molecular targets against ALI in sepsis.
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Lesão Pulmonar Aguda , Vesículas Extracelulares , Precondicionamento Isquêmico , MicroRNAs , Edema Pulmonar , Sepse , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Animais , Vesículas Extracelulares/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The increasing amount of waste produced has been a challenge for human health and the environment, causing a call for effective waste management measures in which household waste separation is of great significance. Although an expanding body of literature has examined the impact of social capital on individual waste-separation behavior, few studies have explicitly discussed the endogeneity problem and the influence mechanisms. Accordingly, our study investigates the effect of social capital on waste-separation behavior and corresponding mechanisms using a national survey dataset of China. The study also reveals the heterogeneity of the influence of individual characteristics on waste-separation behavior. Our results demonstrate that social capital casts a significant positive impact on waste-separation behavior, providing opportunities for individuals' social learning and strengthening the reputation effect. The heterogeneous effects of social capital reveal that women, higher-educated individuals, and political party members present better waste-separation behavior. Besides, the impact of social capital varies between urban and rural areas and among different age groups. Our study provides empirical evidence for policy making of household waste-separation management in developing countries from the perspective of informal institutions.
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Capital Social , Gerenciamento de Resíduos , China , Feminino , HumanosRESUMO
Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.
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Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+ T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+ T cell response to VV infection. In this study, we showed that γδT cells play an important role in promoting CD8+ T cell response to VV infection. We found that γδT cells can directly present viral antigens in the context of MHC-I for CD8+ T cell activation to VV in vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in γδT cells is required for activation of γδT cells and CD8+ T cells. These results illustrate a critical role for γδT cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of γδT cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos Intraepiteliais/imunologia , Vacínia/imunologia , Animais , Apresentação de Antígeno , Antígenos Virais/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vaccinia virusRESUMO
The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ-dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1-knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8+ T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8+ T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.
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Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proteínas Hedgehog/metabolismo , Macrófagos Associados a Tumor/imunologia , Animais , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
Multi-walled carbon nanotubes (MWCNTs) are one of the most widely used types of novel nano-fiber materials. The aim of this study was to establish an experimental system based on actual exposure dosage and environments and explore the roles and mechanisms of inflammation in the malignant transformation of pleural mesothelial cells induced by MWCNTs after low doses and long-term exposure. Here, we established an in vitro system by co-culturing macrophages and mesothelial cells and exposing these cells to high aspect ratio MWCNTs (0.1 µg/mL) for three months. Results indicated that IL-1ß, secreted by macrophages stimulated by MWCNTs, may significantly enhance the release of inflammatory cytokines, such as IL-8, TNF-α, and IL-6, from mesothelial cells. Results obtained from proliferation, migration, invasion, colony formation, and chromosomal aberration studies indicated that MWCNTs may promote malignant transformation of mesothelial cells after long-term and low-dose exposure via inflammation. Furthermore, the obtained results demonstrated that the NF-κB/IL-6/STAT3 pathway was active in the malignant transformation of Met 5A cells, induced by MWCNTs, and played an important role in the process. In conclusion, our results showed that the NF-κB (p65)/IL-6/STAT3 molecular pathway, which was mediated by inflammation, played an important role in the malignant transformation of pleural mesothelial cells induced by MWCNTs. These findings also provide novel ideas and references for the treatment of mesothelioma and offers options for the occupational safety of nanomaterial practitioners.
Assuntos
Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Mesotelioma/imunologia , Nanotubos de Carbono/toxicidade , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Células Epiteliais/imunologia , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Inflamação , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mesotelioma/metabolismo , Mesotelioma/patologia , Mesotelioma Maligno , Células THP-1 , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.
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Linfócitos T CD8-Positivos/citologia , Carcinoma Hepatocelular/imunologia , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/imunologia , Macrófagos/citologia , Animais , Linhagem Celular Tumoral , Linhagem da Célula , Feminino , Células HEK293 , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Fator 4 Semelhante a Kruppel , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/citologia , Transplante de Neoplasias , Fenótipo , Receptores CXCR3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
The activation and recruitment of NK cells to the site of viral infection are crucial for virus control. However, it remains largely unknown what controls the recruitment of the activated NK cells to the infection site. In a model of intraperitoneal infection with vaccinia virus (VV), we showed that poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, is critical for NK cell recruitment to the site of infection and viral control in vivo. We further demonstrated that PARP-1 promotes the production of CCL2 and that the CCL2-CCR2 axis is essential for NK cell recruitment to the infection site. In addition, we demonstrated that peritoneal macrophages are the main producer of PARP-1-dependent CCL2 secretion. Mechanistically, PARP-1 functions as a regulator of NF-κB by promoting its nuclear translocation and binding to its response sequences in macrophages upon VV infection. Taken together, our results reveal a potentially previously unknown role for PARP-1-dependent CCL2 production in NK cell migration and viral control and may provide important insights into the design of effective NK cell-based therapies for viral infections and cancer.
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Células Matadoras Naturais/fisiologia , Doenças Peritoneais/imunologia , Poli(ADP-Ribose) Polimerase-1/fisiologia , Vacínia/imunologia , Animais , Quimiocina CCL2/imunologia , Dano ao DNA , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Doenças Peritoneais/virologia , Vacínia/virologiaRESUMO
PURPOSE: Eyes absent homologue 2 (EYA2), which functions as a transcription activator and phosphatase, plays an important role in several types of cancer. However, the impact of EYA2 in colorectal cancer (CRC) remains elusive. PATIENTS AND METHODS: We evaluated the significance of EYA2 expression in the development and progression of CRC in a large cohort, including 922 CRC cases. EYA2 protein expression was determined via immunohistochemistry in colorectal tissues. The correlation between EYA2 expression and CRC occurrence was investigated in tumor tissue and the adjacent normal tissues. Factors contributing to CRC prognosis were evaluated using Kaplan-Meier and Cox model analyses. RESULTS: EYA2 expression was progressively lower in the adjacent normal tissue, adenomas, primary tumor and the metastatic CRC (all P<0.05). Furthermore, EYA2 expression had significant associations with disease stage, differentiation grade, and number of resected lymph nodes (all P<0.001). Compared with patients with EYA2-high tumors, those with EYA2-low tumors had shorter disease-free survival (hazard ratio [HR], 2.347; 95% CI, 1.665-3.308) and disease-specific survival (HR, 3.560; 95% CI, 2.055-6.167) in multivariate Cox analysis, after adjusting confounding factors such as tumor-node-metastasis stage and grade. In particular, patients with stage II or III EYA2-low CRC might be harmed by postoperative chemotherapy. CONCLUSION: EYA2 expression was generally reduced in CRC. Higher EYA2 expression can predict a more favorable prognosis for CRC.
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Murine tumor models have been critical to advances in our knowledge of tumor physiology and for the development of effective tumor therapies. Essential to these studies is the ability to both track tumor development and quantify tumor burden in vivo. For this purpose, the introduction of genes that confer tumors with bioluminescent properties has been a critical advance for oncologic studies in rodents. Methods of introducing bioluminescent genes, such as firefly luciferase, by viral transduction has allowed for the production of tumor cell lines that can be followed in vivo longitudinally over long periods of time. Here we describe methods for the production of stable luciferase expressing tumor cell lines by lentiviral transduction.
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The polarization of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), especially from the antitumoral phenotype to the protumoral phenotype under certain conditions, has an important influence on the progression of tumors. However, the interactions and combined prognosis of these cells are poorly known. Here, we detected the infiltration of CD68+ TAMs, CD163+ TAMs, and CD66b+ TANs in the specimens from 662 patients with GC by immunohistochemistry. The results showed that the infiltration of each of CD163+ , CD68+ , and CD66b+ cells in GC tissue was significantly increased and independently associated with GC prognosis. Strong collinearity (r = 0.690, P < 0.001) was found between the infiltration of CD163+ and CD68+ cells in GC, and multivariate Cox analysis confirmed the infiltration of CD163+ cells was a better predictor for prognosis than that of CD68+ cells. The combination of the infiltration of CD163+ and CD66b+ cells provided more accurate survival prediction than any individual marker. Patient subgroups with CD66blow CD163low (hazard ratio (HR) = 2.161; 95% confidence interval (CI) = 1.266-3.688; P < 0.001), CD66bhigh CD163high (HR = 3.575; 95% CI = 2.155-5.933; P < 0.001), and CD66blow CD163high (HR = 7.514; 95% CI = 4.583-12.312; P < 0.001) were gradually associated with shorter DFS when compared with the subgroup with CD66bhigh CD163low . The similar result was also for DSS among the subgroups. Moreover, the two-marker model could more effectively discriminate the prognosis among the patients with chemotherapy than that among those without chemotherapy. We concluded that CD163+ TAMs were a more valuable prognostic marker than CD68+ TAMs, and CD163+ TAMs combined with CD66b+ TANs could more precisely predict the prognosis of patients with GC.
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Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Moléculas de Adesão Celular/metabolismo , Macrófagos/imunologia , Neutrófilos/imunologia , Receptores de Superfície Celular/metabolismo , Neoplasias Gástricas/imunologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Recidiva Local de Neoplasia , Infiltração de Neutrófilos , Prognóstico , Análise de Sobrevida , Análise Serial de TecidosRESUMO
Vaccinia virus (VV) can potently activate NK- and T-cell responses, leading to efficient viral control and generation of long-lasting protective immunity. However, immune responses against viral infections are often tightly controlled to avoid collateral damage and systemic inflammation. We have previously shown that granulocytic myeloid-derived suppressor cells (g-MDSCs) can suppress the NK-cell response to VV infection. It remains unknown what regulates T-cell responses to VV infection in vivo. In this study, we first showed that monocytic MDSCs (m-MDSCs), but not g-MDSCs, from VV-infected mice could directly suppress CD4+ and CD8+ T-cell activation in vitro. We then demonstrated that defective recruitment of m-MDSCs to the site of VV infection in CCR2-/- mice enhanced VV-specific CD8+ T-cell response and that adoptive transfer of m-MDSCs into VV-infected mice suppressed VV-specific CD8+ T-cell activation, leading to a delay in viral clearance. Mechanistically, we further showed that T-cell suppression by m-MDSCs is mediated by indication of iNOS and production of NO upon VV infection, and that IFN-γ is required for activation of m-MDSCs. Collectively, our results highlight a critical role for m-MDSCs in regulating T-cell responses against VV infection and may suggest potential strategies using m-MDSCs to modulate T-cell responses during viral infections.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária , Células Supressoras Mieloides/imunologia , Vaccinia virus/imunologia , Transferência Adotiva , Animais , Interferon gama/biossíntese , Interferon gama/imunologia , Interferon gama/farmacologia , Células Matadoras Naturais , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Receptores CCR2/deficiência , Receptores CCR2/metabolismo , Vacínia/virologiaRESUMO
IL-21 has been shown to play an important role in the CD8 T cell response during acute and chronic viral infections. However, the role of IL-21 signaling in the CD4 T cell response to viral infection remains incompletely defined. In a model of infection with vaccinia virus, we show that intrinsic IL-21 signaling on CD4 T cells was critical for the formation of memory CD4 T cells in vivo. We further reveal that IL-21 promoted CD4 T cell survival in a mechanism dependent on activation of the STAT1 and STAT3 signaling pathways. In addition, the activation of Akt is also required for IL-21-dependent survival of CD4 T cells in vivo. These results identify a critical role for intrinsic IL-21 signaling in CD4 T cell survival and memory formation in response to viral infection in vivo and may provide insights into the design of effective vaccine strategies.
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Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Interleucinas/imunologia , Transdução de Sinais , Vacínia/imunologia , Animais , Linfócitos T CD4-Positivos/virologia , Diferenciação Celular , Sobrevivência Celular , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/imunologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologiaRESUMO
NK cells are critical for the control of viral infections. Studies have shown that efficient NK cell activation in response to infection with VV in vivo requires multiple pathways, including the NKG2D pathway. We have recently shown that IL-18 is necessary for the activation of NK cells through upregulation of the NKG2D ligand Rae-1 on DCs upon VV infection. However, how IL-18R signaling on the accessory cells contributes to Rae-1 up-regulation remains to be defined. In this study, we found IL-18-mediated Rae-1 up-regulation in accessory cells, including macrophages and DCs, to be dependent on the MyD88-PI3K pathway. We further found that IL-18 signaling through PI3K led to inhibition of GSK-3, which we found to be a negative regulator of Rae-1. Finally, we demonstrated that in vivo inhibition of GSK-3 could restore Rae-1 up-regulation on IL18R-/- DCs and partially rescue NK-cell activation against VV, leading to improved viral control in IL-18R-/- mice. Our results showed that IL18-dependent Rae-1 up-regulation on accessory cells is mediated by the MyD88-PI3K-GSK3 pathway. These observations may provide important insights into the design of effective NK cell-based immunotherapies.
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Regulação da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Fator 88 de Diferenciação Mieloide/fisiologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Interleucina-18/fisiologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Cultivadas , Feminino , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Viral hepatitis remains a global health challenge despite recent progress in the development of more effective therapies. Although virus-specific CD8+ and CD4+ T cell responses are essential for viral clearance, it remains largely unknown what regulates T cell-mediated viral clearance. Thus, a better understanding of the regulation of anti-viral T cell immunity would be critical for the design of more effective therapies for viral hepatitis. Using a model of adenovirus-induced hepatitis, here we showed that adenoviral infection induced recruitment of Ly6Chi monocytes to the liver in a CCR2-dependent manner. These recruited Ly6Chi monocytes suppressed CD8+ and CD4+ T cell responses to adenoviral infection, leading to a delay in viral clearance. In vivo depletion of Ly6Chi monocytes markedly enhanced anti-viral T cell responses and promoted viral clearance. Mechanistically, we showed that induction of iNOS and the production of NO by Ly6Chi monocytes are critical for the suppression of T cell responses. In addition, a contact-dependent mechanism mediated by PD-1 and PD-L1 interaction is also required for T cell suppression by Ly6Chi monocytes. These findings suggest a critical role for Ly6Chi monocytes in the regulation of T cell immunity in viral hepatitis and may provide new insights into development of more effective therapies for treating viral hepatitis based on targeting the immunosuppressing monocytes.
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Hepatite Viral Animal/imunologia , Monócitos/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/metabolismo , Modelos Animais de Doenças , Fígado/imunologia , Fígado/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores CCR2/imunologiaRESUMO
The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors.
Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Humanos , Imunoterapia , Mesotelioma/imunologia , Camundongos , Linfócitos T/imunologiaRESUMO
OBJECTIVE: To investigate the influence of simvastatin treatment on Toll-like receptor 4 (TLR4) in monocytes of peripheral blood in patients with sepsis and severe sepsis and its significance. METHODS: A prospective randomized controlled trial was conducted. 106 patients with sepsis and 92 patients with severe sepsis admitted to Department of Critical Care Medicine of Henan Provincial People's Hospital from August 2013 to June 2015 were enrolled. These two groups of patients were randomized into conventional treatment group and simvastatin group. All patients received treatment according to the 2012 International Sepsis Treatment Guidelines, including anti-infection drugs, nutritional support, and palliative treatment, and the patients with severe sepsis were given early goal-directed therapy (EGDT). The patients in simvastatin group received simvastatin 40 mg daily orally for at least 15 days. The peripheral blood was collected and the monocytes were isolated at 1, 5, 10, 15 days after intensive care unit (ICU) admission. TLR4 expression on the surface of TLR4/CD14(+) double positive monocytes was determined by flow cytometry, and adverse reaction was observed during treatment. RESULTS: TLR4 expression on the surface of monocytes showed a tendency of decreasing with prolongation of simvastatin treatment in the simvastatin group in patients with sepsis (n = 59) or severe sepsis (n = 54). However, in patients with sepsis, TLR4 level was significantly decreased from 10 days in simvastatin group as compared with that of conventional therapy group (n = 47), and it was decreased up to 15 days [mean fluorescence intensity (MFI): 21 (19, 28) vs. 27 (25, 33) at 10 days, Z = 2.198, P = 0.021; 16 (15, 21) vs. 26 (23, 34) at 15 days, Z = 4.611, P = 0.002]. In patients with severe sepsis, there was no significant difference in TLR4 level at different time points between simvastatin group and conventional treatment group (n = 38) [MFI: 55 (52, 63) vs. 56 (48, 65) at 1 day, Z = 0.313, P = 0.692; 47 (42, 56) vs. 49 (41, 58) at 5 days, Z = 0.827, P = 0.533; 40 (35, 42) vs. 42 (37, 45) at 10 days, Z = 1.012, P = 0.301; 33 (30, 38) vs. 38 (35, 41) at 15 days, Z = 0.539, P = 0.571]. No adverse reaction related with simvastatin was found during treatment in patients with sepsis or severe sepsis. CONCLUSIONS: Statins could significantly down-regulate the TLR4 expression on peripheral blood monocytes in septic patients, while it showed no significant influence on TLR4 expression in patients with severe sepsis. A different effect of statins on TLR4 expression and the downstream inflammation process in sepsis and severe sepsis patients might partially explain the discrepancy in previous reports about the therapeutic effect of statins therapy in sepsis and severe sepsis patients.
Assuntos
Monócitos/efeitos dos fármacos , Sepse/tratamento farmacológico , Sinvastatina/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Regulação para Baixo , Citometria de Fluxo , Humanos , Unidades de Terapia Intensiva , Estudos ProspectivosRESUMO
Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies.