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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, which is lethal in approximately 90% of cases despite advanced standard therapies. A typical feature of PDAC is the immunosuppressive tumor microenvironment with multiple immunosuppressive factors including neurotransmitters. Recently, neuromedin U (NMU), a highly conserved neuropeptide with many physiological functions, has attracted attention for its roles in tumorigenesis and metastasis in several types of cancers. However, whether NMU affects PDAC progression remains unclear. In this study, using an orthotopic mouse model of PDAC in combination with bioinformatics analysis, we found that NMU was upregulated in tumor tissues from the patients with PDAC and positively correlated with a poor prognosis of the disease. Interestingly, knockout of the Nmu gene in mice enhanced the anti-tumor functions of tumor-infiltrating CD8+ T cells in an NMU receptor 1-dependent manner. Additionally, NMU promoted the glycolytic metabolism of mouse PDAC tumors. The activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH), pivotal enzymes involved in the regulation of lactate production, were markedly reduced in tumor tissues from NMU-knockout mice. In vitro the presence of LDHA inhibitor can reduce the production of lactic acid stimulated by NMU, which can increase the anti-tumor activity of CD8+ T cells. Moreover, treatment of the pancreatic cancer cells with a phosphoinositide 3-kinase (PI3K) inhibitor diminished NMU-induced lactate production and the activities of PK and LDH, suggesting that NMU might regulate glycolysis via the PI3K/AKT pathway.
Assuntos
Carcinoma Ductal Pancreático , Neuropeptídeos , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/patologia , Linfócitos T CD8-Positivos/metabolismo , Glicólise , Lactatos , Neuropeptídeos/genética , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Microambiente TumoralRESUMO
Activated group 2 innate lymphoid cells (ILC2s) play a crucial role in respiratory syncytial virus (RSV)-induced airway inflammation and allergy-like symptoms because of their ability to secrete large quantities of type 2 cytokines. Cytokines such as IL-33, IL-25, and thymic stromal lymphopoietin are activators of ILC2s. Besides, a regulatory effect of neurotransmitters on ILC2 activation has been reported recently. However, whether and how RSV infection induces neurotransmitter production in the lungs and regulates pulmonary ILC2 activation remains unclear. In this study, using a murine model established by intranasal infection with RSV, we found that acute RSV infection induced the production of a neurotransmitter, neuromedin U (NMU), in the lungs of RSV-infected mice and upregulated the expression of NMUR1 (neuromedin U receptor 1) on ILC2s. Moreover, in vivo administration of NMU exacerbated RSV-induced airway inflammation by promoting the proliferation and activation of pulmonary ILC2s via the NMUR1 pathway, which involved PI3K, mitogen-activated protein kinase kinase, and NFAT signaling proteins. Furthermore, pulmonary neurons responded to the stimulation of RSV infection and secreted NMU in a Toll-like receptor 4- and Toll-like receptor 7-dependent manner. Collectively, our data suggest that NMU is a powerful neuropeptide to activate ILC2s, highlighting the critical regulatory effects of neurotransmitters on antiviral, inflammatory, and tissue homeostasis at the mucosal barrier during a viral respiratory infection.
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Neuropeptídeos , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Animais , Camundongos , Imunidade Inata , Linfócitos/metabolismo , Pulmão/metabolismo , Citocinas/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , InflamaçãoRESUMO
Nearly 3 × 1013 types of bacteria colonize the human intestine. These colonized bacteria help in maintaining intestinal homeostasis by establishing a complex relationship with the intestinal epithelium and lymphoid tissue. Alteration in the composition of the intestinal microbiota is associated with susceptibility to various pathological conditions, such as autoimmune disorders, diabetes, inflammation and cancer. Of late, several researchers have focused on examining the effects of gut microbiota on the outcome of various cancer treatment protocols. Side effects and complications of traditional chemotherapy and allogeneic hematopoietic cell transplantation are associated with intestinal dysbiosis. Gut microbiota affects the efficacy of immune checkpoint inhibitor-based immunotherapy. The gut is inhabited by diverse resident bacteria, of which, few enhance, while others inhibit the host response to immunotherapy. This review focuses on the correlation between intestinal microbiota and the outcome of tumor immunotherapy. Additionally, the molecular mechanisms underlying the effects of gut microbiota on the efficacy of cancer immunotherapy have been reviewed. Further studies are needed for the identification of distinct gut microbiota and their efficacy in tumor immunotherapy as certain types of intestinal bacteria could function as novel adjuvant drugs to enhance the effectiveness of antitumor therapy in humans.
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Triple-negative breast cancer (TNBC) is an invasive breast cancer with the characteristics of easy to develop distant metastasis. Immune escape is one of the main reasons for TNBC growth and metastasis. Enhancement of T cell-mediated anti-tumor activity may benefit to inhibit tumor metastasis and improve the efficacy of cancer therapy. As a natural bioactive substance, resveratrol shows potential capability to prevent or suppress the development of a variety of cancers through direct or indirect effects, including immunoregulatory effect. However, whether resveratrol might affect lung metastasis of TNBC, and whether the effect of resveratrol might be associated with resveratrol-regulated immune responses in tumor microenvironment is still unknown. In this study, by using an experimental metastatic mouse 4 T1 tumor model, we identified that resveratrol may suppress TNBC lung metastasis by elevating local anti-tumor immunity. Indeed, an increase in the cytotoxic activity of CD8+T cells as well as the levels of type 1 cytokine IFN-γ and IL-2 in the lungs of resveratrol-treated tumor bearing mice were observed. The enhanced CD8+T cell activity and Th1 immune responses by resveratrol administration might be related to the down-regulated PD-1 expression on pulmonary CD8+T cells and CD4+T cells. Resveratrol may also convert macrophages to M1 phenotype in the lungs of tumor bearing mice. However, it seems likely resveratrol has no effect on pulmonary myeloid-derived suppressor cell activation. Our results provide an evidence that resveratrol might be a promising candidate agent for adjuvant therapy in the process of TNBC metastasis.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/imunologia , Macrófagos/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Resveratrol/uso terapêutico , Células Th1/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Metástase Neoplásica , Neoplasias de Mama Triplo Negativas/patologia , Evasão TumoralRESUMO
Age at primary infection with respiratory syncytial virus (RSV) is a crucial factor in determining the outcome of reinfection. However, how neonatal RSV infection affects the immune system and renders the host more susceptible to reinfection in later life is poorly understood. In the present study, by using BALB/c mice that were first infected with RSV as neonates, the role of γδ T cells in the development of airway inflammation during reinfection in adulthood was investigated. We found that neonatal RSV infection resulted in an aggravated infiltration of mononuclear cells in bronchoalveolar lavage (BAL) fluids, in parallel with a significant increase in the levels of type 2 cytokines in lungs on day 4 after reinfection. Since the numbers of total γδ T cells as well as activated γδ T cells, particularly IL-4-, IL-5-, and IL-13-producing γδ T cells, were enhanced markedly in the lungs of neonatally primed mice, we speculate that γδ T cells might participate in the augmented airway inflammation seen during reinfection. Indeed, depletion of γδ T cells attenuated the severity of lung histopathology during reinfection. Meanwhile, treatment of neonatal mice with anti-TCRδ mAb diminished not only the numbers of neutrophils, eosinophils, and lymphocytes, but also the levels of IL-4, IL-5, and IL-13 in the lungs after reinfection in adulthood, suggesting that γδ T cells, particularly Th2-type γδ T cells might play a critical role in exacerbating the pulmonary tissue pathology during reinfection of adult mice that were first infected as neonates.
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Inflamação/imunologia , Pulmão/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções Respiratórias/imunologia , Subpopulações de Linfócitos T/imunologia , Fatores Etários , Animais , Animais Recém-Nascidos , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Interleucina-13/imunologia , Interleucina-4/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva , Infecções por Vírus Respiratório Sincicial/patologia , Infecções Respiratórias/virologia , Subpopulações de Linfócitos T/metabolismo , Células Th2/imunologiaRESUMO
It is well accepted that vaccination by oral administration has many advantages over injected parenteral immunization. The present study focuses on whether oral vaccination with a DNA vaccine could induce protective immunity against respiratory challenge infection. The M1 gene of influenza A virus was used to construct DNA vaccine using pcDNA 3.1(+) plasmid, a eukaryotic expression vector. The cationic liposomes were used to deliver the constructed DNA vaccine. In vitro and in vivo expression of M1 gene was observed in the cell line and in the intestine of orally vaccinated C57BL/6 mice, respectively. It became clear that this type of oral DNA vaccination was capable of inducing both humoral and cellular immune responses, together with an augmentation of IFN-γ production. In addition, oral vaccination with liposome-encapsulated DNA vaccine could protect the mice against respiratory challenge infection. These results suggest that gastrointestinal tract, a constituent member of the common mucosal immune system, is a potent candidate applicable as a DNA vaccine route against virus respiratory diseases.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Lipossomos/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Administração Oral , Animais , Anticorpos Antivirais/sangue , Modelos Animais de Doenças , Vacinas contra Influenza/genética , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vacinas de DNA/genética , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/imunologiaRESUMO
BACKGROUND: It has been reported that adoptive transfer of γδ T cells increases the cellular infiltration, especially eosinophils, in the lungs of allergic mice, suggesting that γδ T cells may play a proinflammatory role in allergic airway inflammation. Respiratory syncytial virus (RSV) infection can decrease the number of Th2-type γδ T cells. However, the underlying mechanisms remain unknown. METHODS: BALB/c mice were inoculated intranasally with RSV before or after sensitization to OVA. The amounts of Th1/Th2 cytokines as well as the levels of specific antibodies were determined by ELISA. The apoptotic death of pulmonary γδ T cells was analyzed by flow cytometry. RESULTS: Adoptive transfer of γδ T cells increased the production of Th2 cytokines in the lungs and allergy-related antibodies in the serum, further confirming that γδ T cells act as pro-inflammatory cells or a promoter for the development of allergic asthma. RSV infection before sensitization to OVA enhanced apoptotic death of pulmonary γδ T cells. The percentage and absolute number of FasL-expressing γδ T cells in the lungs of allergic mice were elicited significantly by prior RSV infection. Blocking FasL with monoclonal antibody diminished apoptotic death of γδ T cells, suggesting that FasL is important for RSV-induced apoptosis of pulmonary γδ T cells. CONCLUSIONS: This work provides evidence that RSV infection suppresses the subsequent development of OVA-induced allergic responses partly by enhancing FasL-mediated apoptosis of pulmonary γδ T cells.
Assuntos
Proteína Ligante Fas/imunologia , Pneumonia/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/virologia , Alérgenos , Análise de Variância , Animais , Apoptose/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Feminino , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/farmacologia , Pneumonia/fisiopatologia , Distribuição Aleatória , Valores de Referência , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Vírus Sinciciais Respiratórios/patogenicidade , Infecções Respiratórias/imunologia , Infecções Respiratórias/fisiopatologia , Medição de Risco , Sensibilidade e Especificidade , Células Th2/imunologiaRESUMO
Introduction: Zhusha Anshen Wan (ZSASW) is a traditional Chinese medicine compound mainly composed of mineral drugs. In clinical practice, ZSASW did not show the toxicity of administering equal doses of cinnabar alone, suggesting that the four combination herbs in ZSASW can alleviate the damage of cinnabar. The effect of each herb on reducing the toxicity of cinnabar has not been fully explained. Methods: In our study, we utilized a metabonomics approach based on high-resolution 1H nuclear magnetic resonance spectroscopy to investigate the reduction of toxicity by each herb in ZSASW. Liver, kidney and intestinal histopathology examinations and biochemical analysis of the serum were also performed. Results: Partial least squares-discriminant analysis (PLS-DA) was conducted to distinct different metabolic profiles in the urine and serum from the rats. Liver and kidney histopathology examinations, as well as analysis of serum clinical chemistry analysis, were also carried out. The metabolic profiles of the urine and serum of the rats in the CGU (treated with cinnabar and Glycyrrhiza uralensis Fisch) and CCC (treated with cinnabar and Coptis chinensis French) groups were remarkably similar to those of the control group, while those of the CRG (treated with cinnabar and Rehmannia glutinosa Libosch) and CAS (treated with cinnabar and Angelica sinensis) groups were close to those of the cinnabar group. The metabolic profiles of the urine and serum of the rats in the CGU and CCC groups were remarkably similar to those of the control group, while those of the CRG and CAS groups were close to those of the cinnabar group. Changes in endogenous metabolites associated with toxicity were identified. Rehmannia glutinosa, Rhizoma Coptidis and Glycyrrhiza uralensis Fisch could maintain the dynamic balance of the intestinal flora. These results were also verified by liver, kidney and intestinal histopathology examinations and biochemical analysis of the serum. The results suggested that Discussion: The metabolic mechanism of single drug detoxification in compound prescriptions has been elucidated. Coptis chinensis and Glycyrrhiza uralensis serve as the primary detoxification agents within ZSASW for mitigating liver, kidney, and intestinal damage caused by cinnabar. Detoxification can be observed through changes in the levels of various endogenous metabolites and related metabolic pathways.
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Respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans still remain inconclusive. The association between RSV infection and allergic diseases may be dependent on an atopic background and previous history of RSV infection. It has been reported that RSV infection before sensitization to an allergen decreased the production of Th2-like cytokines in the lung and the levels of allergen-specific Th2-type antibodies in the serum. However, the underlying mechanisms are largely unknown. In the present study, the role of pulmonary γδ T cells in RSV-affected, allergen-induced airway inflammation was investigated. BALB/c mice were sensitized to or challenged with ovalbumin (OVA) and infected with RSV either before or after the sensitization period. It became clear that sensitization and challenge of mice with OVA induced a large influx of γδ T cells to the lungs. However, prior RSV infection inhibited the infiltration of γδ T cells as well as activated γδ T cells, characterized by expression of CD40L or CD69 molecular in the cell surface. Moreover, prior RSV infection elevated the type 1 cytokine gene expression but suppressed type 2 cytokine expression in the lung γδ T cells. Adoptive transfer of γδ T cells from OVA-sensitized and challenged mice increased airway inflammation, suggesting that γδ T cells may play a proinflammatory role in allergic responses. These results described here support the idea of an unknown γδ T cell-dependent mechanism in the regulation of RSV-affected, allergen-induced allergic airway responses.
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Hipersensibilidade/imunologia , Tolerância Imunológica , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Serpinas/imunologia , Células Th2/imunologia , Animais , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Ligante de CD40/análise , Citocinas/biossíntese , Feminino , Perfilação da Expressão Gênica , Lectinas Tipo C/análise , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Antígenos de Linfócitos T gama-delta/análise , Vírus Sinciciais Respiratórios/imunologia , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/imunologia , Células Th2/químicaRESUMO
Studies have proven that gut microbiota dysbiosis may influence the carcinogenesis and outcomes of multiple cancers. However, it is still unclear whether gut microbiota dysbiosis affect the progression of breast cancer, especially triple-negative breast cancer. In the present study, by using gut microbiota dysbiosis murine model established by treatment of mice with streptomycin, we found Lactobacillus and the metabolite-lactic acid are the pivotal factors for 4T1 tumor progression. In fact, streptomycin-treated mice exhibited slower tumor growth, in parallel with less abundance of Lactobacillus in the gut. Supplementation with Lactobacillus resulted in a rapid tumor growth, following a decrease in the expression of mRNAs for anti-tumor-related factors but an increase in the M2 polarization. The elevated percentages of IFN-γ-producing CD4+T cells and CD8+T cells in the tumor microenvironment of streptomycin-treated tumor-bearing mice may be vanished by supplementation of Lactobacillus. It seems likely that lactobacillus-mediated pro-tumor effect is related to the production of lactic acid. A decrease in the levels of lactic acid in the cecal feces and tumor tissues were observed in streptomycin-treated tumor bearing mice. However, supplementation of Lactobacillus can restore streptomycin-reduced concentration of lactic acid in the tumor tissues, suggesting that gut Lactobacillus are the source of lactic acid. Bioinformatics analysis result suggests high concentration of lactic acid in tumor sites may be related to the diminished anti-tumor immunity in the TME. This study reveals a correlation between gut Lactobacillus and tumor progression in a murine 4T1 tumor model, providing experimental evidence for clinical treatment of breast cancer.
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Lactobacillus , Neoplasias , Camundongos , Animais , Lactobacillus/metabolismo , Disbiose , Estreptomicina/uso terapêutico , Estreptomicina/metabolismo , Ácido Láctico/uso terapêutico , Microambiente TumoralRESUMO
Respiratory syncytial virus (RSV) infection induces the activation of CD4+ T cells. However, the underlying mechanism of CD4+T-cell activation induced by RSV infection is not fully understood. In the present study, we found that depletion of CD4+ T cells can obviously reduce airway inflammation caused by RSV infection. Meanwhile, adoptive transfer of group 2 innate lymphocytes (ILC2s) significantly enhanced the number of CD4+ T cells and promoted their differentiation to Th2 in lung. In fact, RSV infection increased the expression of major histocompatibility complex-II (MHC II) molecules on the surface of pulmonary ILC2s. In vitro coculture experiments showed that ILC2s may act as promoters to promote the expansion and differentiation of RSV-infected CD4+ T cells. However, blocking the interaction between CD4+ T cells and ILC2s with anti-MHC-II mAbs significantly reduced CD4+T-cell expansion. These results suggest that pulmonary ILC2s may function as antigen-presenting cells to induce the activation of CD4+ T cells through the MHC II pathway during RSV infection.
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Infecções por Vírus Respiratório Sincicial , Animais , Camundongos , Linfócitos T CD4-Positivos , Antígenos de Histocompatibilidade Classe II , Imunidade Inata , Pulmão , Complexo Principal de Histocompatibilidade , Camundongos Endogâmicos BALB C , Linfócitos TRESUMO
BACKGROUND: Over 10% of entire population in Japan suffer from allergic diseases induced by Japanese cedar pollen (JCP) every spring. In terms of preventive medicine, it has become a matter of urgency to establish successful prophylactic and therapeutic strategies for controlling the disorders. The effect of an oligodeoxynucleotide containing a cytidine-guanosine motif (CpG ODN) on the regulation of immune responses induced by JCP was investigated in this study. METHODS: BALB/c mice were inoculated with CpG ODN intraperitoneally before intranasal sensitization to JCP. Cellular infiltration in the lung of BALB/c mice after treatment with CpG ODN or JCP was performed by hematoxylin and eosin (H&E) staining. Antibody titers and cytokines levels were determined by ELISA. RESULTS: Intranasal inoculation of BALB/c mice with JCP induced a T-helper type 2 (Th2-type) dominant immune response, as characterized by the production of interleukin (IL)-4 and IL-5 in the lung and of JCP-specific IgE antibody in serum. Prior intraperitoneal administration of CpG ODN to mice suppressed the subsequent JCP-induced antibody production and infiltration of inflammatory cells in the lung. The inhibitory mechanism of CpG ODN seemed to be attributable to a CpG ODN-induced Th1-type dominant environment, which down-regulated Th2-type response subsequently induced by JCP allergen sensitization. Furthermore, administration with CpG ODN decreased the production of JCP-induced IL-17, which has been found to play a pivotal role in several inflammatory diseases including allergic asthma. The decreased production of IL-17, together with reduced secretion of IL-4 and IL-5, may contribute to diminish the inflammation in the lung of JCP-sensitized mice. CONCLUSION: This work provides evidence that the CpG ODN has a prophylactic effect on the JCP-induced Th2-type allergic responses by establishing or restoring a Th1-type shift of immune environments.
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Alérgenos/efeitos adversos , Cryptomeria , Citidina/uso terapêutico , Fosfatos de Dinucleosídeos/uso terapêutico , Guanosina/uso terapêutico , Oligodesoxirribonucleotídeos/uso terapêutico , Pólen , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Células Th2/imunologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Group 2 innate lymphoid cells (ILC2s) are reportedly associated with the progression of many tumors. However, the role of ILC2s in triple-negative breast cancer (TNBC) lung metastasis remains unclear. In this study, we found that ILC2s may be a key element in the process of TNBC lung metastasis since the adoptive transfer of pulmonary ILC2s increased the numbers of metastatic lung nodules and reduced the survival of tumor-bearing mice. ILC2-promoted 4 T1 lung metastasis appears to be related to ILC2-derived IL-13. An expansion of IL-13-producing ILC2s and an elevated expression of IL-13 mRNA in pulmonary ILC2s were determined in tumor-bearing mice, in parallel with an increase in the levels of local IL-13 by ILC2 transfer. The neutralization of IL-13 reduced the increased pulmonary metastatic nodules and improved the decreased survival rate caused by ILC2-adoptive transfer. Interestingly, adoptive transfer of ILC2s elevated IL-13Ra1 expression in myeloid-derived suppressor cells (MDSCs). Treatment of ILC2-transferred tumor-bearing mice with anti-IL-13 antibodies significantly diminished the number of pulmonary MDSCs and inhibited MDSC activation. Moreover, when pulmonary MDSCs were cocultured with ILC2s in the presence of an anti-IL-13 mAb, the number and activation of MDSCs were reduced. Depletion of MDSCs may promote the proliferation of CD4+ T cells and CD8+ T cells, but reduce the expansion of regulatory T cells (Tregs) in the lungs of ILC2-transferred tumor-bearing mice. Our results suggest that pulmonary ILC2s may promote TNBC lung metastasis via the ILC2-derived IL-13-activated MDSC pathway.
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Interleucina-13/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/genética , Citocinas/imunologia , Feminino , Imunidade Inata , Pulmão/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos BALB C , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Changes in the intestinal microbiota indirectly impact the health of mucosa distal to the intestine, particularly the respiratory tract. However, the effects of intestinal microbiota dysbiosis on the regulation of respiratory syncytial virus (RSV) infection are not clear. In this study, we examined the effects of altering the intestinal microbiota on the pulmonary immune response against RSV infection. BALB/c mice were treated with streptomycin before infection with RSV to study the altered immune response. The ingestion of streptomycin led to a marked alteration in the intestinal microbiota with a reduced abundance of Lactobacillus and Clostridium genera, followed by greatly aggravated pulmonary inflammation in response to RSV infection. This aggravated inflammation was associated with a dysregulated immune response against RSV infection, characterized by the increased expression of IFN-γ and IL-17 and increased pulmonary M1-like macrophage polarization, and decreased expression of IL-5. Supplementation of Clostridium butyricum (CB) prevented aggravated inflammation and the dysregulated immune response characterized by greater M2 polarization of pulmonary macrophages and decreased release of IFN-γ and IL-17 as well as increased IL-5 levels. Furthermore, in vitro and in vivo experiments identified that butyrate, the main metabolite produced by CB, promoted M2 polarization of macrophages in RSV-infected mice exposed to streptomycin. Together, these results demonstrate the mechanism by which intestinal microbiota modulate the pulmonary immune response to RSV infection.
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Clostridium butyricum , Microbioma Gastrointestinal , Pneumonia Viral , Infecções por Vírus Respiratório Sincicial , Administração Oral , Animais , Disbiose , Inflamação , Interferon gama/imunologia , Interleucina-17/imunologia , Interleucina-5/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Viral/terapia , Infecções por Vírus Respiratório Sincicial/terapia , Vírus Sincicial Respiratório Humano , EstreptomicinaRESUMO
BACKGROUND: Liver fibrosis progression is commonly found in patients with CHB. Liver biopsy is a gold standard for identifying the extent of liver fibrosis, but has many draw-backs. It is essential to construct a noninvasive model to predict the levels of risk for liver fibrosis. It would provide very useful information to help reduce the number of liver biopsies of CHB patients. METHODS: 339 chronic hepatitis B patients with HBsAg-positive were investigated retrospectively, and divided at random into 2 subsets with twice as many patients in the training set as in the validation set; 116 additional patients were consequently enrolled in the study as the testing set. A three-layer artificial neural network was developed using a Bayesian learning algorithm. Sensitivity and ROC analysis were performed to explain the importance of input variables and the performance of the neural network. RESULTS: There were 329 patients without significant fibrosis and 126 with significant fibrosis in the study. All markers except gender, HB, ALP and TP were found to be statistically significant factors associated with significant fibrosis. The sensitivity analysis showed that the most important factors in the predictive model were age, AST, platelet, and GGT, and the influence on the output variable among coal miners were 22.3-24.6%. The AUROC in 3 sets was 0.883, 0.884, and 0.920. In the testing set, for a decision threshold of 0.33, sensitivity and negative predictive values were 100% and all CHB patients with significant fibrosis would be identified. CONCLUSIONS: The artificial neural network model based on routine and serum markers would predict the risk for liver fibrosis with a high accuracy. 47.4% of CHB patients at a decision threshold of 0.33 would be free of liver biopsy and wouldn't be missed.
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Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Cirrose Hepática/diagnóstico , Redes Neurais de Computação , Medição de Risco , Adolescente , Adulto , Idoso , Biomarcadores , Feminino , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Distribuição Aleatória , Adulto JovemRESUMO
Spinal cord injury (SCI) is a traumatic condition of the central nervous system (CNS) that can cause paralysis of the limbs. The molecular mechanisms of neural repair following SCI remain unclear and no effective treatment for SCI currently exists, since drugs have difficulty crossing the blood-brain barrier (BBB). The present study aimed to investigate whether exosomes could be used as specific carriers of resveratrol for induction of neuronal autophagy both in vitro and in vivo for the treatment of SCI. The results indicate that exosomes are able to enhance the solubility of resveratrol and enhance penetration of the drug through the BBB, thereby increasing its concentration in the CNS. Exosomes derived from resveratrol-treated primary microglia (Exo + Res) assisted the rehabilitation of paralyzed limbs in rats. Restoration of neural function following SCI was mediated through increased induction of autophagy and inhibition of apoptosis of neurons both in vitro and in vivo via activation of the PI3K signaling pathway. The mechanism of action of Exo + Res may be associated with the PI3K inhibitor 3-methyladenine (3-MA) in primary spinal neurons. The results suggest that Exo + Res are highly effective at crossing the BBB with good stability, suggesting they have potential for enhancing targeted drug delivery and the recovery of neuronal function in SCI therapy, likely associated with the induction of autophagy and inhibition of apoptosis via the PI3K signaling pathway.
Assuntos
Portadores de Fármacos , Exossomos , Recuperação de Função Fisiológica/efeitos dos fármacos , Resveratrol/administração & dosagem , Traumatismos da Medula Espinal/patologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Masculino , Microglia/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/metabolismoRESUMO
CD4+T cells are crucial cellular source of type 2 cytokines and responsible for RSV-induced asthma-like symptoms and asthma exacerbations. However, the mechanism for regulating the activation of CD4+T cells during RSV infection is not clear completely. We show in this study that infection with RSV may induce an expansion and activation of CD4+T cells in the lungs of BALB/c mice. RSV-induced CD4+T cell expansion and activation seems to depend upon the pulmonary group 2 innate lymphoid cells (ILC2s), since adoptive transfer of lung ILC2s can enhance not only the numbers of CD4+T cells but also the cytokine production by CD4+T cells. Interestingly, blockade of the contact between ILC2s and CD4+T cells, may significantly diminish the CD4+T cell expansion and cytokine production, suggesting that membrane molecules may be involved in ILC2-regulated CD4+T cell activation. In fact, infection with RSV resulted in an increase in the numbers of OX40+CD4+T cells as well as OX40L+ILC2s in the lungs of mice. Moreover, the mRNA expressions of OX40 and OX40L as well as the levels of OX40 and OX40L proteins in the lung CD4+T cells and ILC2s were elevated respectively. When co-culture of CD4+T cells with ILC2s in the presence of anti-OX40L antibody, the cytokine productions by CD4+T cells were reduced markedly, suggesting that lung ILC2s may regulate RSV-induced CD4+T cell expansion and activation perhaps via OX40/OX40L interaction.
Assuntos
Pulmão/citologia , Pulmão/imunologia , Linfócitos/imunologia , Ligante OX40/imunologia , Receptores OX40/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Técnicas de Cocultura , Citocinas/imunologia , Feminino , Imunidade Inata , Camundongos Endogâmicos BALB C , Baço/citologiaRESUMO
Aim: To investigate whether and how CD4+ T cells contribute to ILC2 activation during respiratory syncytial virus (RSV) infection. Methods: The methods of flow cytometry, quantitative PCR and ELISA were used in the present study. Results: Depletion of CD4+ T cells diminished the numbers of lung ILC2s as well as their ability to produce type 2 cytokines. CD4+ T cell-mediated ILC2 activation is related to IL-2. The main cellular source of IL-2 was CD4+ T cells. Depletion of CD4+ T cells decreased IL-2 levels in the lungs of RSV-infected mice. IL-2 can directly stimulate ILC2 proliferation and promote ILC2s to produce cytokines. Treatment of mice with neutralizing anti-IL-2 monoclonal antibodies diminished ILC2 activation. Conclusion: These results suggest that CD4+ T cells contribute to RSV-induced ILC2 activation partly via producing IL-2.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunidade Inata/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
AIM: How respiratory syncytial virus (RSV) influences the development of ovalbumin (OVA)-induced asthma remains elusive. As potent T helper (Th)2 cytokine producers, group 2 innate lymphoid cells (ILC2s) are known to serve important functions in the pathogenesis of allergic inflammation. However, how RSV infection affects innate immunity, especially with regard to the function of ILC2s in OVA-induced allergic airway inflammation, is largely unknown. MATERIALS & METHODS: RSV was used to infect adult BALB/c mice intranasally prior to sensitization and subsequent challenge with OVA. ILC2 frequencies and Th2 cytokine production by ILC2s were assessed by flow cytometry. Cytokine levels were detected both by real-time PCR and ELISA. RESULTS: Previous infection with RSV attenuated airway inflammation and decreased Th2 cytokine production in mice sensitized and challenged with OVA. Furthermore, previous infection with RSV inhibited the influx of ILC2s into the lung, and constrained their Th2 cytokine production. Adoptive transfer of ILC2s increased asthma-associated airway inflammation in mice previously infected with RSV. These results indicate that previous infection with RSV prevents OVA-induced asthma development via inhibition of ILC2s. Previous infection with RSV attenuated IL-33 production in lung tissue and reduced relative ST2L expression in lung ILC2s, meaning that previous infection with RSV may alter ILC2 function via the IL-33/ST2 signaling pathway. CONCLUSION: These results demonstrate that previous infection with RSV attenuates OVA-induced airway inflammation by inhibiting the recruitment and Th2 cytokine production of ILC2s via the IL-33/ST2 pathway.
Assuntos
Hipersensibilidade/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Pulmão/imunologia , Linfócitos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/fisiologia , Alérgenos/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Pulmão/virologia , Camundongos , Ovalbumina/imunologia , Transdução de Sinais , Células Th2/imunologiaRESUMO
AIM: To investigate the clinical significance of the levels of IL-4, IL-33 and thymic stromal lymphopoietin (TLSP) in patients with asthma and/or rhinitis, then do the simple verification in animals. METHODS: Levels of IL-4 IL-31, IL-33 and TLSP were detected by ELISA and real-time PCR in 64 asthma patients (sIgE[+]: 32 cases, sIgE[-]: 32 cases), 64 rhinitis patients (sIgE[+]: 32 cases, sIgE[-]: 32 cases), 64 asthma complicated with allergic rhinitis patients (sIgE[+]: 32 cases, sIgE[-]: 32 cases) and 32 healthy controls. Then we detected the IL-4, IL-31, IL-33 and TLSP in the sensitized mice. RESULTS: Results showed that levels of IL-4, IL-31, IL-33 and TSLP in asthma and rhinitis patients, and those complicated with allergic rhinitis, had significant differences compared with the control group (p < 0.05). It was found that the indicators of mugwort and dust mite allergic patients were significantly higher than that of other allergic patients (p < 0.05). We got the same tendency in in vivo experiments. CONCLUSION: IL-4, IL-31, IL-33 and TSLP may be involved in the pathogenesis of asthma and rhinitis; dust mite and mugwort allergy could increase them significantly.