RESUMO
BACKGROUND: The incidence of composite endpoint of early safety (CEES) after transcatheter aortic valve replacement (TAVR) has been a topic of focus within the cardiovascular field due to its impact on long-term patient outcomes. Timely prophylactic interventions are crucial for patients identified as high risk for CEES through preoperative risk stratification. OBJECTIVES: This study aimed to explore the connection between inflammatory and nutritional markers, specifically the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI), and CEES occurrence. MATERIAL AND METHODS: A cohort of 134 patients undergoing TAVR in a single center was studied. The study endpoint was the occurrence of CEES, which was defined according to the Valve Academic Research Consortium 3. RESULTS: The CEES was reached in 25.4% of patients at 30 days. A high NLR was associated with a 5.55-fold increased risk of CEES (95% confidence interval (95% CI): 1.52-20.29; p < 0.05), while a low PNI was linked to a 4.43-fold increased risk (95% CI: 1.55-12.65; p < 0.01). Combining NLR and PNI provided additional risk stratification for high-risk patients (hazard ratio (HR), 95% CI: 2.24-43.37; p < 0.005). CONCLUSIONS: A high NLR and low PNI were shown to be significant predictors of CEES following TAVR. These findings underscore the significance of NLR and PNI in the risk assessment of TAVR patients, offering valuable insights for preventive measures.
Assuntos
Infecções Relacionadas a Cateter , Humanos , Fatores de Risco , Masculino , Feminino , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/etiologia , Adulto , Pessoa de Meia-Idade , Cateterismo Periférico/efeitos adversos , Estudos Retrospectivos , Idoso , Adulto Jovem , Adolescente , Leucemia Mieloide Aguda/complicações , Doença Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaçõesRESUMO
AIM: To analyze the sequencing results of circular RNAs (circRNAs) in cardiomyocytes between the doxorubicin (DOX)-injured group and exosomes treatment group. Moreover, to offer potential circRNAs possibly secreted by exosomes mediating the therapeutic effect on DOX-induced cardiotoxicity for further study. METHODS: The DOX-injured group (DOX group) of cardiomyocytes was treated with DOX, while an exosomes-treated group of injured cardiomyocytes were cocultured with bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BEC group). The high-throughput sequencing of circRNAs was conducted after the extraction of RNA from cardiomyocytes. The differential expression of circRNA was analyzed after identifying the number, expression, and conservative of circRNAs. Then, the target genes of differentially expressed circRNAs were predicted based on the targetscan and Miranda database. Next, the GO and KEGG enrichment analyses of target genes of circRNAs were performed. The crucial signaling pathways participating in the therapeutic process were identified. Finally, a real-time quantitative polymerase chain reaction experiment was conducted to verify the results obtained by sequencing. RESULTS: Thirty-two circRNAs are differentially expressed between the two groups, of which twenty-three circRNAs were elevated in the exosomes-treated group (BEC group). The GO analysis shows that target genes of differentially expressed circRNAs are mainly enriched in the intracellular signalactivity, regulation of nucleic acid-templated transcription, Golgi-related activity, and GTPase activator activity. The KEGG analysis displays that they were involved in the autophagy biological process and NOD-like receptor signaling pathway. The verification experiment suggested that mmu_circ_0000425 (ID: 116324210) was both decreased in the DOX group and elevated in BEC group, which was consistent with the result of sequencing. CONCLUSION: mmu_circ_0000425 in exosomes derived from bone marrow mesenchymal stem cells (BMSC) may have a therapeutic role in alleviating doxorubicin-induced cardiotoxicity (DIC).
Assuntos
Doxorrubicina , Exossomos , Células-Tronco Mesenquimais , Miócitos Cardíacos , RNA Circular , RNA Circular/genética , RNA Circular/metabolismo , Doxorrubicina/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Exossomos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/citologia , Animais , Perfilação da Expressão Gênica , Ratos , Células CultivadasRESUMO
Toll-like receptors (TLRs) play an important role in inducing innate and acquired immune responses against infection. However, the effect of Toll-like receptor 7 (TLR7) on follicular helper T (Tfh) cells in mice infected with Plasmodium is still not clear. The results showed that the splenic CD4+ CXCR5+ PD-1+ Tfh cells were accumulated after Plasmodium yoelii NSM infection, the content of splenic Tfh cells was correlated to parasitemia and/or the red blood cells (RBCs) counts in the blood. Moreover, the expression of TLR7 was found higher than TLR2, TLR3 and TLR4 in splenic Tfh cells of the WT mice. TLR7 agonist R848 and the lysate of red blood cells of infected mice (iRBCs) could induce the activation and differentiation of splenic Tfh cells. Knockout of TLR7 leads to a decrease in the proportion of Tfh cells, down-regulated expression of functional molecules CD40L, IFN-γ, IL-21 and IL-10 in Tfh cells; decreased the proportion of plasma cells and antibody production and reduces the expression of STAT3 and Ikzf2 in Tfh cells. Administration of R848 could inhibit parasitemia, enhance splenic Tfh cell activation and increase STAT3 and Ikzf2 expression in Tfh cells. In summary, this study shows that TLR7 could regulate the function of Tfh cells, affecting the immune response in the spleen of Plasmodium yoelii NSM-infected mice.
Assuntos
Malária , Plasmodium yoelii , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia/metabolismo , Plasmodium yoelii/metabolismo , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Auxiliares-Indutores , Receptor 7 Toll-Like/metabolismoRESUMO
IMPORTANCE: This is the first report that a human E3 ubiquitin ligase, Casitas B-lineage lymphoma proto-oncogene B (Cbl-b), functions as a host dependency factor for the intracellular protozoan Toxoplasma gondii and the mechanism for how T. gondii infection inhibits the TLR/MyD88 innate immunity pathway through MyD88 degradation mediated by Cbl-b. This finding is an impactful contribution for understanding the host cell immunity against T. gondii infection.
Assuntos
Fator 88 de Diferenciação Mieloide , Toxoplasma , Humanos , Imunidade Inata , Ubiquitina-Proteína LigasesRESUMO
CD103 is an important marker of tissue-resident memory T cells (TRM) which play important roles in fighting against infection. However, the immunological characteristics of CD103+ T cells are not thoroughly elucidated in the liver of mouse infected with Plasmodium. Six- to eight-week-old C57BL/6 mice were infected with Plasmodium yoelii nigeriensis NSM. Mice were sacrificed on 12-16 days after infection and the livers were picked out. Sections of the livers were stained, and serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were measured. Moreover, lymphocytes in the liver were isolated, and the expression of CD103 was determined by using qPCR. The percentage of CD103 on different immune cell populations was dynamically observed by using flow cytometry (FCM). In addition, the phenotype and cytokine production characteristics of CD103+CD8+ Tc cell were analyzed by using flow cytometry, respectively. Erythrocyte stage plasmodium infection could result in severe hepatic damage, a widespread inflammatory response and the decrease of CD103 expression on hepatic immune cells. Only CD8+ Tc and γδT cells expressed higher levels of CD103 in the uninfected state.CD103 expression in CD8+ Tc cells significantly decreased after infection. Compared to that of CD103- CD8+ Tc cells, CD103+ CD8+ Tc cells from the infected mice expressed lower level of CD69, higher level of CD62L, and secreted more IL-4, IL-10, IL-17, and secreted less IFN-γ. CD103+CD8+ Tc cells might mediate the hepatic immune response by secreting IL-4, IL-10, and IL-17 except IFN-γ in the mice infected with the erythrocytic phase plasmodium, which could be involved in the pathogenesis of severe liver damage resulted from the erythrocytic phase plasmodium yoelii nigeriensis NSM infection.
Assuntos
Malária , Plasmodium yoelii , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Interleucina-10/metabolismo , Interleucina-17 , Interleucina-4 , Fígado , Malária/imunologia , Malária/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Objective To investigate the effect of T cell immunoreceptor with Ig and ITIM domains (TIGIT) on the function of CD8+ T cells in the lungs of Plasmodium infected mice. Methods The lungs of the mice infected with Plasmodium yoelii were isolated, weighed and photographed after 12 days' infection. After dissolution, lung lymphocytes were isolated, counted and stained, and then the contents of CD8+ and TIGIT+CD8+ T cells were detected by flow cytometry. The expressions of L selectin (CD62L), CD69, programmed death 1 (PD-1), CD25, and C-X3-C motif chemokine receptor 1 (CX3CR1) on TIGIT+CD8+ T cells were detected by flow cytometry. After stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, the ability of TIGIT+CD8+T cells to secrete interferon γ(IFN-γ), interleukin 21 (IL-21), IL-4, IL-17, and IL-10 was detected. Results The body mass of mice with Plasmodium infection was reduced. The lungs became darker, and the ratio of the lung mass to body mass was significantly increased. Compared with the normal mice, the percentages and absolute quantity of CD8+ and TIGIT+CD8+ T cells in the lungs of the infected mice were significantly increased. The percentage of TIGIT+CD8+ T cells expressing CD62L in the infected group was significantly lower, while the percentage of the CD69, PD-1, and CX3CR1 cells were significantly higher than that of TIGIT+CD8+ T cells from the normal mice. The percentages of TIGIT+CD8+ T cells secreting IL-21, IL-4, IL-17 and IL-10 cells in the infected group were significantly lower. Conclusion The lung lesions from mice with Plasmodium infection are obvious, the numbers of TIGIT+CD8+ T cells increase, and these cells express a variety of activation-related molecules, but the ability to secrete cytokines is reduced.
Assuntos
Malária , Plasmodium yoelii , Animais , Camundongos , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Malária/metabolismo , Plasmodium yoelii/metabolismo , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Splenomegaly is a prominent clinical manifestation of malaria and the causes remain incompletely clear. Anemia is induced in malaria and extramedullary splenic erythropoiesis is compensation for the loss of erythrocytes. However, the regulation of extramedullary splenic erythropoiesis in malaria is unknown. An inflammatory response could facilitate extramedullary splenic erythropoiesis in the settings of infection and inflammation. Here, when mice were infected with rodent parasites, Plasmodium yoelii NSM, TLR7 expression in splenocytes was increased. To explore the roles of TLR7 in splenic erythropoiesis, we infected wild-type and TLR7 -/- C57BL/6 mice with P. yoelii NSM and found that the development of splenic erythroid progenitor cells was impeded in TLR7 -/- mice. Contrarily, the treatment of the TLR7 agonist, R848, promoted extramedullary splenic erythropoiesis in wild-type infected mice, which highlights the implication of TLR7 on splenic erythropoiesis. Then, we found that TLR7 promoted the production of IFN-γ that could enhance phagocytosis of infected erythrocytes by RAW264.7. After phagocytosis of infected erythrocytes, the iron metabolism of RAW264.7 was upregulated, evidenced by higher iron content and expression of Hmox1 and Slc40a1. Additionally, the neutralization of IFN-γ impeded the extramedullary splenic erythropoiesis modestly and reduced the iron accumulation in the spleen of infected mice. In conclusion, TLR7 promoted extramedullary splenic erythropoiesis in P. yoelii NSM-infected mice. TLR7 enhanced the production of IFN-γ, and IFN-γ promoted phagocytosis of infected erythrocytes and the iron metabolism of macrophages in vitro, which may be related to the regulation of extramedullary splenic erythropoiesis by TLR7.
Assuntos
Malária , Baço , Camundongos , Animais , Baço/metabolismo , Eritropoese , Receptor 7 Toll-Like , Camundongos Endogâmicos C57BL , Interferon gama/uso terapêutico , Macrófagos/metabolismo , Ferro/metabolismoRESUMO
Introduction of a fluorine-containing block into block copolymers is an effective method to tune block copolymer nanoassemblies with a microphase-separated structure. However, this microphase-separated structure is difficult to clearly observe due to its nanoscale size. In this work, fluorine-containing ABC triblock copolymer vesicles of poly(ethylene glycol)-block-polystyrene-block-poly(4-vinylbenzyl pentafluorophenyl ether) (PEG-b-PS-b-PVBFP) are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization under dispersed condition. Owing to the choice of a suitable degree of polymerization of the three blocks, the synthesized PEG45-b-PS197-b-PVBFP233 vesicles have a relatively large size of around 216 nm and a thin vesicular membrane with a thickness of around 28 nm. Ascribed to the relatively large size of the vesicles and the thin vesicular membrane, it is concluded that the fluorine-containing PVBFP block forms 9 nm columnar microdomains shielded by the PS phase in the vesicular membrane.
RESUMO
Toll-like receptors (TLRs) play an important role in the induction of innate and adaptive immune responses against Schistosoma japonicum (S. japonicum) infection. However, the role of Toll-like receptor 7 (TLR7) in the mouse lung during S. japonicum infection and the myeloid-derived suppressor cells (MDSCs) affected by the absence of TLR7 are not clearly understood. In this study, the results indicated that the MDSCs were accumulated and the proportion and activation of CD4+ and CD8+ T cells were decreased in the lung of mice at 6-7 weeks after S. japonicum infection. Then, the expression of TLR7 was detected in isolated pulmonary MDSCs and the results showed that the expression of TLR7 in MDSCs was increased after infection. Furthermore, TLR7 agonist R848 could down-regulate the induction effect of the soluble egg antigen (SEA) on pulmonary MDSCs in vitro. Meanwhile, TLR7 deficiency could promote the pulmonary MDSCs expansion and function by up-regulating the expression of PD-L1/2 and secreting of IL-10 in the mice infected with S. japonicum. Mechanistic studies revealed that S. japonicum infection and the antigen effects are mediated by NF-κB signaling. Moreover, TLR7 deficiency aggravates S. japonicum infection-induced damage in the lung, with more inflammatory cells infiltration, interstitial dilatation and granuloma in the tissue. In summary, this study indicated that TLR7 signaling inhibits the accumulation and function of MDSCs in S. japonicum infected mouse lung by down-regulating the expression of PD-L1/2 and secreting of IL-10, via NF-κB signaling.
Assuntos
Células Supressoras Mieloides , Esquistossomose Japônica , Receptor 7 Toll-Like , Animais , Camundongos , Antígeno B7-H1/metabolismo , Interleucina-10/metabolismo , Pulmão , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/metabolismo , NF-kappa B , Schistosoma japonicum/fisiologia , Esquistossomose Japônica/imunologia , Receptor 7 Toll-Like/metabolismoRESUMO
The morbidity and mortality of malaria are still high. Programmed cell death-1(PD-1) is an important co-inhibitory factor and CD8 T cells with PD-1 were reported to be exhausted cells. It remains unknown what the role of CD4 T cells expressing PD-1 is and what the upstream regulating molecules of PD-1 in CD4 T cells are. The C57BL/6 mice were injected with Plasmodium yoelii (P. yoelii) in this study. Expressions of PD-1, activation markers, and cytokines were tested. The differentially expressed genes between PD-1+/- CD4 T cells were detected by microarray sequencing. Western blot, chromatin immunoprecipitation (ChIP), siRNA, hypoxia inducible factor-1α (HIF-1α) inducer and inhibitor were used to explore PD-1's upstream molecules, respectively. The proportions of PD-1+ CD4 T cells increased post P. yoelii infection. PD-1+ CD4 T cells expressed more activated surface markers and could produce more cytokines. Nuclear factor of activated T cells 1 (NFATc1) was found to be a key transcription factor to induce PD-1 expression after infection. Both the inducer and the inhibitor of HIF-1α could change the expressions of NFATc1 and PD-1 in vivo and in vitro, respectively. Taken together, P. yoelii infection induced NFATc1 expression by HIF-1α. The highly expressed NFATc1 entered the nucleus and initiated PD-1 expression. PD-1+ CD4 T cells appeared to be more activated and could secrete more cytokines to regulate the host's immune responses against malaria.
Assuntos
Linfócitos T CD4-Positivos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Malária , Fatores de Transcrição NFATC , Plasmodium yoelii , Receptor de Morte Celular Programada 1 , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de SinaisRESUMO
OBJECTIVE: To explore the genetic basis for a child presented with renal failure and multi-cystic dysplastic kidney without anal atresia. METHODS: Peripheral blood sample of the child and his parents were collected and subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: The 40-day-old infant had presented with vomiting brown matter in a 7 days neonate and was transferred for kidney failure. Clinical examination has discovered renal failure, polycystic renal dysplasia, congenital hypothyroidism, bilateral thumb polydactyly, sensorineural hearing loss and preauricular dermatophyte. Genetic testing revealed that he has harbored a previously unreported c.824delT, p.L275Yfs*10 frameshift variant of SALL1 gene, which was confirmed by Sanger sequencing as de novo. CONCLUSION: The patient was diagnosed with Townes-Brocks syndrome due to the novel de novo variant of SALL1 gene. Townes-Brocks syndrome without anal atresia is rare. Above finding has also enriched the mutational spectrum of the SALL1 gene.
Assuntos
Anus Imperfurado , Perda Auditiva Neurossensorial , Insuficiência Renal , Anormalidades Múltiplas , Anus Imperfurado/diagnóstico , Anus Imperfurado/genética , Criança , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Recém-Nascido , Masculino , Polegar/anormalidades , Fatores de Transcrição/genéticaRESUMO
A systematic review was conducted on the literature on feeding behaviors in Chinese families of children under 6 years old. Forty relevant publications were identified, of which 33 were published in Chinese, 7 in English. All studies were questionnaire-based and used a cross-sectional research design. Approximately half of the studies reported a score for each feeding practice/style, based on a Likert scale; the other half dichotomized these scores into a percentage of the population that reported frequent use of the behaviors. The most commonly reported feeding style of Chinese caregivers was a locally defined "active response" style that somewhat resembled authoritative parenting. The most commonly reported feeding practices were praise, encouraging trying new foods, encouragement of balanced diet and encouragement of healthy eating. Some behaviors showed a great deal of variance in prevalence between studies, which may be at least partially due to differences in methodology and how behaviors were defined. Some feeding behaviors varied in frequency depending on the child's age, although longitudinal studies are needed to better understand how these evolve over time. Child body composition was also associated with feeding behaviors use, although the direction of the association cannot be determined due to the cross-sectional nature of the research. There is still an important gap in the literature regarding the feeding behaviors of non-maternal caregivers, as grandparents often play an important role in childcare in China.
Assuntos
Comportamento Alimentar , Poder Familiar , Povo Asiático , Criança , Pré-Escolar , Estudos Transversais , Humanos , Lactente , Inquéritos e QuestionáriosRESUMO
B cells played an important role in Schistosoma infection-induced diseases. TLR7 is an intracellular member of the innate immune receptor. The role of TLR7 on B cells mediated immune response is still unclear. Here, C57BL/6 mice were percutaneously infected by S. japonicum for 5-6 weeks. The percentages and numbers of B cells increased in the infected mice (p < 0.05), and many activation and function associated molecules were also changed on B cells. More splenic cells of the infected mice expressed TLR7, and B cells were served as the main cell population. Moreover, a lower level of soluble egg antigen (SEA) specific antibody and less activation associated molecules were found on the surface of splenic B cells from S. japonicum infected TLR7 gene knockout (TLR7 KO) mice compared to infected wild type (WT) mice (p < 0.05). Additionally, SEA showed a little higher ability in inducing the activation of B cells from naive WT mice than TLR7 KO mice (p < 0.05). Finally, the effects of TLR7 on B cells are dependent on the activation of NF-κB p65. Altogether, TLR7 was found modulating the splenic B cell responses in S. japonicum infected C57BL/6 mice.
Assuntos
Linfócitos B/imunologia , Schistosoma japonicum/fisiologia , Esquistossomose Japônica/imunologia , Baço/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Schistosoma japonicum/genética , Esquistossomose Japônica/genética , Esquistossomose Japônica/parasitologia , Baço/parasitologia , Receptor 7 Toll-Like/genéticaRESUMO
S. japonicum infection can induce granulomatous inflammation in the liver of the host. Granulomatous inflammation limits the spread of infection and plays a role in host protection. Toll-like receptor 7 (TLR7) is an endosomal TLR that recognizes single-stranded RNA (ssRNA). In this study, the role of TLR7 in S. japonicum infection-induced hepatitis was investigated in both normal and TLR7 knockout (KO) C57BL/6 mice. The results indicated that TLR7 KO could aggravate S. japonicum infection-induced damage in the body, with less granuloma formation in the tissue, lower WBCs in blood, and decreased ALT and AST in the serum. Then, the expression of TLR7 was detected in isolated hepatic lymphocytes. The results indicated that the percentage of TLR7+ cells was increased in the infected mice. Hepatic macrophages, DCs, and B cells could express TLR7, and most of the TLR7-expressing cells in the liver of infected mice were macrophages. The percentage of TLR7-expressing macrophages was also increased after infection. Moreover, macrophages, T cells, and B cells showed significant changes in the counts, activation-associated molecule expression, and cytokine secretion between S. japonicum-infected WT and TLR7 KO mice. Altogether, this study indicated that TLR7 could delay the progression of S. japonicum infection-induced hepatitis mainly through macrophages. DCs, B cells, and T cells were involved in the TLR7-mediated immune response.
Assuntos
Fígado/parasitologia , Esquistossomose Japônica , Receptor 7 Toll-Like , Animais , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Schistosoma japonicum , Esquistossomose Japônica/imunologiaRESUMO
Background: Th cells (helper T cells) have multiple functions in Schistosoma japonicum (S. japonicum) infection. Inducible co-stimulator (ICOS) is induced and expressed in activated T lymphocytes, which enhances the development of B cells and antibody production through the ICOS/ICOSL pathway. It remains unclear about the role and possible regulating mechanism of ICOS+ Th cells in the spleen of S. japonicum-infected C57BL/6 mice. Methods: C57BL/6 mice were infected with cercariae of S. japonicum through the abdomen. The expression of ICOS, activation markers, and the cytokine production on CD4+ ICOS+ Th cells were detected by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR). Moreover, the differentially expressed gene data of ICOS+ and ICOS- Th cells from the spleen of infected mice were obtained by mRNA sequencing. Besides, Western blot and chromatin immunoprecipitation (ChIP) were used to explore the role of Ikzf2 on ICOS expression. Results: After S. japonicum infection, the expression of ICOS molecules gradually increased in splenic lymphocytes, especially in Th cells (P < 0.01). Compared with ICOS- Th cells, more ICOS+ Th cells expressed CD69, CD25, CXCR5, and CD40L (P < 0.05), while less of them expressed CD62L (P < 0.05). Also, ICOS+ Th cells expressed more cytokines, such as IFN-γ, IL-4, IL-10, IL-2, and IL-21 (P < 0.05). RNA sequencing results showed that many transcription factors were increased significantly in ICOS+ Th cells, especially Ikzf2 (P < 0.05). And then, the expression of Ikzf2 was verified to be significantly increased and mainly located in the nuclear of ICOS+ Th cells. Finally, ChIP experiments and dual-luciferase reporter assay confirmed that Ikzf2 could directly bind to the ICOS promoter in Th cells. Conclusion: In this study, ICOS+ Th cells were found to play an important role in S. japonicum infection to induce immune response in the spleen of C57BL/6 mice. Additionally, Ikzf2 was found to be one important transcription factor that could regulate the expression of ICOS in the spleen of S. japonicum-infected C57BL/6 mice.
Assuntos
Fator de Transcrição Ikaros/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Ativação Linfocitária , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/parasitologia , Baço/parasitologia , Linfócitos T Auxiliares-Indutores/parasitologia , Animais , Sítios de Ligação , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita , Fator de Transcrição Ikaros/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Schistosoma japonicum/imunologia , Esquistossomose Japônica/genética , Esquistossomose Japônica/imunologia , Esquistossomose Japônica/metabolismo , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
The accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles to achieve an appropriate anti-tumor immune response and successful tumor immunotherapy. MDSCs in tumor-bearing hosts are primarily polymorphonuclear (PMN-MDSCs). However, the mechanisms regulating the development of MDSCs remain poorly understood. In this report, we showed that interferon regulatory factor 4 (IRF4) plays a key role in the development of PMN-MDSCs, but not monocytic MDSCs. IRF4 deficiency caused a significant elevation of PMN-MDSCs and enhanced the suppressive activity of PMN-MDSCs, increasing tumor growth and metastasis in mice. Mechanistic studies showed that c-Myc was up-regulated by the IRF4 protein. Over-expression of c-Myc almost abrogated the effects of IRF4 deletion on PMN-MDSCs development. Importantly, the IRF4 expression level was negatively correlated with the PMN-MDSCs frequency and tumor development but positively correlated with c-Myc expression in clinical cancer patients. In summary, this study demonstrated that IRF4 represents a novel regulator of PMN-MDSCs development in cancer, which may have predictive value for tumor progression.
Assuntos
Fatores Reguladores de Interferon/fisiologia , Células Supressoras Mieloides/fisiologia , Neoplasias/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Transcrição Gênica , Animais , Proliferação de Células , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-myc/fisiologiaRESUMO
BACKGROUND: Malaria has high morbidity and mortality rates in some parts of tropical and subtropical countries. Besides respiratory and metabolic function, lung plays a role in immune system. γδT cells have multiple functions in producing cytokines and chemokines, regulating the immune response by interacting with other cells. It remains unclear about the role of γδT cells in the lung of mice infected by malaria parasites. METHODS: Flow cytometry (FCM) was used to evaluate the frequency of γδT cells and the effects of γδT cells on the phenotype and function of B and T cells in Plasmodium yoelii-infected wild-type (WT) or γδTCR knockout (γδT KO) mice. Haematoxylin-eosin (HE) staining was used to observe the pathological changes in the lungs. RESULTS: The percentage and absolute number of γδT cells in the lung increased after Plasmodium infection (p < 0.01). More γδT cells were expressing CD80, CD11b, or PD-1 post-infection (p < 0.05), while less γδT cells were expressing CD34, CD62L, and CD127 post-infection (p < 0.05). The percentages of IL-4+, IL-5+, IL-6+, IL-21+, IL-1α+, and IL-17+ γδT cells were increased (p < 0.05), but the percentage of IFN-γ-expressing γδT cells decreased (p < 0.05) post-infection. The pathological changes in the lungs of the infected γδT KO mice were not obvious compared with the infected WT mice. The proportion of CD3+ cells and absolute numbers of CD3+ cells, CD3+ CD4+ cells, CD3+ CD8+ cells decreased in γδT KO infected mice (p < 0.05). γδT KO infected mice exhibited no significant difference in the surface molecular expression of T cells compared with the WT infected mice (p > 0.05). While, the percentage of IFN-γ-expressing CD3+ and CD3+ CD8+ cells increased in γδT KO infected mice (p < 0.05). There was no significant difference in the absolute numbers of the total, CD69+, ICOS+, and CD80+ B cells between the WT infected and γδT KO infected mice (p > 0.05). CONCLUSIONS: The content, phenotype, and function of γδT cells in the lung of C57BL/6 mice were changed after Plasmodium infection. γδT cells contribute to T cell immune response in the progress of Plasmodium infection.
Assuntos
Linfócitos Intraepiteliais/imunologia , Pulmão/imunologia , Malária/imunologia , Plasmodium yoelii/fisiologia , Animais , Linfócitos B/imunologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologiaRESUMO
BACKGROUND: Many kinds of immune cells are involved in malaria infection. γδT cells represent a special type of immune cell between natural and adaptive immune cells that play critical roles in anti-parasite infection. METHODS: In this study, malaria infection model was constructed. Distribution of γδT cells in various immune organs and dynamic changes of γδT cells in the spleens of C57BL/6 mice after infection were detected by flow cytometry. And activation status of γδT cells was detected by flow cytometry. Then γδT cells in naive and infected mice were sorted and performed single-cell RNA sequencing (scRNA-seq). Finally, γδTCR KO mice model was constructed and the effect of γδT cell depletion on mouse T and B cell immunity against Plasmodium infection was explored. RESULTS: Here, splenic γδT cells were found to increase significantly on day 14 after Plasmodium yoelii nigeriensis NSM infection in C57BL/6 mice. Higher level of CD69, ICOS and PD-1, lower level of CD62L, and decreased IFN-γ producing after stimulation by PMA and ionomycin were found in γδT cells from infected mice, compared with naive mice. Moreover, 11 clusters were identified in γδT cells by scRNA-seq based t-SNE analysis. Cluster 4, 5, and 7 in γδT cells from infected mice were found the expression of numerous genes involved in immune response. In the same time, the GO enrichment analysis revealed that the marker genes in the infection group were involved in innate and adaptive immunity, pathway enrichment analysis identified the marker genes in the infected group shared many key signalling molecules with other cells or against pathogen infection. Furthermore, increased parasitaemia, decreased numbers of RBC and PLT, and increased numbers of WBC were found in the peripheral blood from γδTCR KO mice. Finally, lower IFN-γ and CD69 expressing CD4+ and CD8+ T cells, lower B cell percentage and numbers, and less CD69 expressing B cells were found in the spleen from γδTCR KO infected mice, and lower levels of IgG and IgM antibodies in the serum were also observed than WT mice. CONCLUSIONS: Overall, this study demonstrates the diversity of γδT cells in the spleen of Plasmodium yoelii nigeriensis NSM infected C57BL/6 mice at both the protein and RNA levels, and suggests that the expansion of γδT cells in cluster 4, 5 and 7 could promote both cellular and humoral immune responses.
Assuntos
Malária , Plasmodium yoelii , Animais , Linfócitos T CD8-Positivos , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , ParasitemiaRESUMO
High glucose metabolism is recognized as one of the hallmarks of cancer and increased expression levels of several key factors involved in glucose metabolism have been reported in non-small cell lung cancer (NSCLC). Previous studies showed that microRNA (miR)-218 is reduced in NSCLC, but its function in glucose metabolism in NSCLC is not fully understood. The present study aimed to investigate the effect of miR-218 on glucose metabolism in NSCLC cell lines and the underlying molecular mechanism. The present results suggested that miR-218 reduced glucose consumption, the mechanism of glycolysis and activity in the pentose phosphate pathway. In addition, glucose transporter 1 (GLUT1) was identified to be a direct target of miR-218, while overexpression of GLUT1 did not abolish the effect of miR-218 on glucose metabolism. The present results indicated that phosphorylation of NF-κB p65 was significantly decreased by miR-218 in NSCLC cells and that activation of NF-κB led to the inhibition of miR-218 regulation of glucose metabolism. In conclusion, the present results suggested that miR-218 downregulated glucose metabolism in NSCLC not only by directly targeting GLUT1, but also via the NF-κB signaling pathway.