T cell immunoglobulin and mucin domain 3 (Tim-3) is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to ide...T cell immunoglobulin and mucin domain 3 (Tim-3) is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to identify the relationship between Tim-3 expression and post-burn T cells immune suppression, C57BL/6 mice were subjected to burn injury or sham injury, and the liver and spleen were harvested at the day 1 after operation. The expression level of Tim-3 on hepatic or splenic T cells and the functional properties of Tim-3+ T cells were evaluated. It was found burn injury induced dramatically elevated Tim-3 expression on both hepatic and splenic CD4+ and CD8+ T cells in contrast with the post-burn depletion of T cells. Furthermore, Tim-3 expression was correlated with the suppressive phenotype of T cells following burn injury, including increased expression of anti-inflammatory cytokine IL-10, decreased expression of pro-inflammatory cytokines IFN-γ and TNF-α, reduced T cell proliferation and elevated co-expression of Tim-3 and PD-1. Moreover, Tim-3+ T cells subsets were more prone to spontaneous apoptosis than Tim-3- T cells subsets. Our findings reinforce the idea that the up-regulated expression of Tim-3 on T cells after burn injury plays an important role in the development and maintenance of burn-induced T cell immune suppression.展开更多
Background Four-chambered stomach including the forestomachs(rumen,reticulum,and omasum)and abomasum allows ruminants convert plant fiber into high-quality animal products.The early development of this four-chambered ...Background Four-chambered stomach including the forestomachs(rumen,reticulum,and omasum)and abomasum allows ruminants convert plant fiber into high-quality animal products.The early development of this four-chambered stomach is crucial for the health and well-being of young ruminants,especially the immune development.However,the dynamics of immune development are poorly understood.Results We investigated the early gene expression patterns across the four-chambered stomach in Hu sheep,at 5,10,15,and 25 days of age.We found that forestomachs share similar gene expression patterns,all four stomachs underwent widespread activation of both innate and adaptive immune responses from d 5 to 25,whereas the metabolic function were significantly downregulated with age.We constructed a cell landscape of the four-chambered stomach using single-cell sequencing.Integrating transcriptomic and single-cell transcriptomic analyses revealed that the immune-associated module hub genes were highly expressed in T cells,monocytes and macrophages,as well as the defense-associated module hub genes were highly expressed in endothelial cells in the four-stomach tissues.Moreover,the non-immune cells such as epithelial cells play key roles in immune maturation.Cell communication analysis predicted that in addition to immune cells,non-immune cells recruit immune cells through macrophage migration inhibitory factor signaling in the forestomachs.Conclusions Our results demonstrate that the immune and defense responses of four stomachs are quickly developing with age in lamb's early life.We also identified the gene expression patterns and functional cells associated with immune development.Additionally,we identified some key receptors and signaling involved in immune regulation.These results help to understand the early life immune development at single-cell resolution,which has implications to develop nutritional manipulation and health management strategies based on specific targets including key receptors and signaling pathways.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most common malignancies worldwide,and its development comprises a multistep process from intraepithelial neoplasia(IN)to carcinoma(CA).However,the crit...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most common malignancies worldwide,and its development comprises a multistep process from intraepithelial neoplasia(IN)to carcinoma(CA).However,the critical regulators and underlying molecular mechanisms remain largely unknown.AIM To explore the genes and infiltrating immune cells in the microenvironment that are associated with the multistage progression of ESCC to facilitate diagnosis and early intervention.METHODS A mouse model mimicking the multistage development of ESCC was established by providing warter containing 4-nitroquinoline 1-oxide(4NQO)to C57BL/6 mice.Moreover,we established a control group without 4NQO treatment of mice.Then,transcriptome sequencing was performed for esophageal tissues from patients with different pathological statuses,including low-grade IN(LGIN),high-grade IN(HGIN),and CA,and controlled normal tissue(NOR)samples.Differentially expressed genes(DEGs)were identified in the LGIN,HGIN,and CA groups,and the biological functions of the DEGs were analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The CIBERSORT algorithm was used to detect the pattern of immune cell infilt-ration.Immunohistochemistry(IHC)was also conducted to validate our results.Finally,the Luminex multiplex cytokine analysis was utilized to measure the serum cytokine levels in the mice.RESULTS Compared with those in the NOR group,a total of 681541,and 840 DEGs were obtained in the LGIN,HGIN,and CA groups,respectively.Using the intersection of the three sets of DEGs,we identified 86 genes as key genes involved in the development of ESCC.Enrichment analysis revealed that these genes were enriched mainly in the keratinization,epidermal cell differentiation,and interleukin(IL)-17 signaling pathways.CIBERSORT analysis revealed that,compared with those in the NOR group,M0 and M1 macrophages in the 4NQO group showed stronger infiltration,which was validated by IHC.Serum cytokine analysis revealed that,compared with those in the NOR group,IL-1βand IL-6 were upregulated,while IL-10 was downregulated in the LGIN,HGIN,and CA groups.Moreover,the expression of the representative key genes,such as S100a8 and Krt6b,was verified in external human samples,and the results of immunohistochemical staining were consistent with the findings in mice.CONCLUSION We identified a set of key genes represented by S100a8 and Krt6b and investigated their potential biological functions.In addition,we found that macrophage infiltration and abnormal alterations in the levels of inflam-mation-associated cytokines,such as IL-1β,IL-6,and IL-10,in the peripheral blood may be closely associated with the development of ESCC.展开更多
Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation(allo-HSCT)has been widely implemented to treat hematologic malignancies.However,graft-versus-host d...Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation(allo-HSCT)has been widely implemented to treat hematologic malignancies.However,graft-versus-host disease(GVHD)and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life.In addition,GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions(DLIs)and chimeric antigen receptor(CAR)T-cell therapy.Because of the special immune tolerance characteristics and anti-tumor ability of universal immune cells,universal immune cell therapy may strongly reduce GVHD,while simultaneously reducing tumor burden.Nevertheless,widespread application of universal immune cell therapy is mainly restricted by poor expansion and persistence efficacy.Many strategies have been applied to improve universal immune cell proliferation and persistence efficacy,including the use of universal cell lines,signaling regulation and CAR technology.In this review we have summarized current advances in universal immune cell therapy for hematologic malignancies with a discussion of future perspectives.展开更多
Tanshinone IIA,one of the main ingredients of Danshen,is used to treat hepatocellular carcinoma(HCC).However,potential targets of the molecule in the therapy of HCC are unknown.Methods:In this study,we collected the t...Tanshinone IIA,one of the main ingredients of Danshen,is used to treat hepatocellular carcinoma(HCC).However,potential targets of the molecule in the therapy of HCC are unknown.Methods:In this study,we collected the tanshinone IIA targets from public databases for investigation.We screened differentially expressed genes(DEGs)across HCC and normal tissues using mRNA expression profiles from The Cancer Genome Atlas(TCGA).Univariate Cox regression analysis and least absolute shrinkage and selection operator(LASSO)Cox regression models were used to identify and construct the prognostic gene signature.Results:Finally,we discovered common genes across tanshinone IIA targets and HCC DEGs.We reported Fatty acid binding protein-6(FABP6),Polo-like Kinase 1(PLK1),deoxythymidylate kinase(DTYMK),Uridine Cytidine Kinase 2(UCK2),Enhancer of Zeste Homolog 2(EZH2),and Cytochrome P4502C9(CYP2C9)as components of a gene signature.The six-gene signature’s prognostic ability was evaluated using the Kaplan-Meier curve,time-dependent receiver operating characteristic(ROC),multivariate Cox regression analysis,and the nomogram.The mRNA level and protein expression of UCK2 were experimentally validated after treatment with different concentrations of tanshinone IIA in HEPG2 cells.CIBERSORTx,TIMER2.0,and GEPIA2 tools were employed to explore the relationship between the prognostic signature and immune cell infiltration.Conclusion:We established a six-gene signature as a reliable model with significant therapeutic possibility for prognosis and overall survival estimation in HCC patients,which might also benefit medical decision-making for appropriate treatment.展开更多
As the largest internal organ of the human body,the liver has an extremely complex vascularnetwork and multiple types of immune cells.It plays an important role in blood circulation,material metabolism,and immune resp...As the largest internal organ of the human body,the liver has an extremely complex vascularnetwork and multiple types of immune cells.It plays an important role in blood circulation,material metabolism,and immune response.Optical imaging is an effective tool for studying finevascular structure and immunocyte distribution of the liver.Here,we provide an overview of thestructure and composition of liver vessels,the threedimensional(3D)imaging of the liver,andthe spatial distribution and immune function of various cell components of the liver.Especially,we emphasize the 3D imaging methods for visualizing fine structure in the liver.Finally,wesummarize and prospect the development of 3D imaging of liver vesels and immune cells.展开更多
We have found that the expression of ring finger and WD repeat domain 3(RFWD3)is significantly higher in unpaired and paired hepatocellular carcinoma(HCC)tissues than in normal tissues.Moreover,this expression has a s...We have found that the expression of ring finger and WD repeat domain 3(RFWD3)is significantly higher in unpaired and paired hepatocellular carcinoma(HCC)tissues than in normal tissues.Moreover,this expression has a significant correlation with the infiltration level of 14 immune cell types and when the detected RFWD3 expression levels were grouped as high and low,a prominent difference was revealed for overall survival,disease-specific survival,and progression-free interval.Through statistical analysis(univariate Cox),we were also able to identify RFWD3 as an independent prognostic element for HCC,with RFWD3 having an ability to accurately predict HCC prognosis(area under the curve of 0.863).Finally,we have generated prognostic nomograms for probabilities of 1-,3-and 5-year overall survival in HCC via integrating the factors of age,pathologic stage,alpha-fetoprotein level,and RFWD3 expression.展开更多
BACKGROUND Spindle and kinetochore-associated complex subunit 3(SKA3)is a malignancyassociated gene that plays a critical role in the regulation of chromosome separation and cell division.However,the molecular mechani...BACKGROUND Spindle and kinetochore-associated complex subunit 3(SKA3)is a malignancyassociated gene that plays a critical role in the regulation of chromosome separation and cell division.However,the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma(HCC)has not been fully elucidated.AIM To investigate the molecular mechanisms underlying the role of SKA3 in HCC.METHODS SKA3 expression,clinicopathological,and survival analyses were performed using multiple public database platforms,and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples.Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC.Furthermore,the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis(ssGSEA)algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC.The response to chemotherapeutic drugs was evaluated by the R package“pRRophetic”.RESULTS We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC.Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival.GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair.Moreover,patients with high SKA3 expression had significantly decreased ratios of CD8+T cells,natural killer cells,and dendritic cells.Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib,sunitinib,paclitaxel,doxorubicin,gemcitabine,and vx-680.CONCLUSION High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC.SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.展开更多
Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflamm...Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.展开更多
BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mecha...BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.展开更多
Background: A major cause of cancer death worldwide is bladder cancer, which is the most common malignant tumor of the urinary tract. PAEP is a member of the kernel lipocalin superfamily whose members share relatively...Background: A major cause of cancer death worldwide is bladder cancer, which is the most common malignant tumor of the urinary tract. PAEP is a member of the kernel lipocalin superfamily whose members share relatively low sequence similarity but have highly conserved exon/intron structure and three-dimensional protein folding. Most lipocalins are clustered on the long arm of chromosome 9. The purpose of this study was to clarify the correlation between PAEP expression level and bladder cancer. Methods: In the TCGA database, we obtained clinical and RNA sequencing data of 431 BLCA patients, including 412 BLCA tissues and 19 normal bladder tissues in the study. Analyses of bioinformatics were conducted in this study to determine the role of PAEP in bladder cancer. A quantitative real-time PCR method was used to quantitate the gene expression profile. Additionally, the effect of PAEP on tumor immune infiltration and prognosis was analyzed. Results: PAEP was a poor prognostic biomarker of bladder cancer because it was significantly upregulated. bladder cancer patients with higher PAEP expression had poor outcomes. An AUC of 0.780 was calculated from the area under the ROC curve. PAEP was associated with T stage, pathologic stage, Histologic grade and Subtype of bladder cancer patients, and served as an independent predictor of overall survival in bladder cancer patients. Functional enrichment analysis revealed PAEP was obviously enriched in pathways connected with carcinogenesis and immunosuppression. The expression of PAEP was significantly associated with tumor immune cells and immune checkpoints according to ssGSEA and Spearman correlation analysis. Conclusions: In this study, we screened and detected a mRNA, PAEP is a prognostic and immune-related biomarker in BLCA, which may contribute to the early diagnosis and treatment of BLCA.展开更多
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some p...Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding the pathogenesis of NAFLD is of great clinical importance and is critical for the prevention and treatment of the disease. Although the "two-hit hypothesis" is generally accepted, the exact pathogenesis of NAFLD has not been clearly established. The liver is an important innate immune organ with large numbers of innate immune cells, including Kupffer cells (KCs), natural killer T (NKT) cells and natural killer (NK) cells. Recent data show that an imbalance in liver cytokines may be implicated in the development of fatty liver disease. For example, Th1 cytokine excess may be a common pathogenic mechanism for hepatic insulin resistance and NASH. Innate immune cells in the liver play important roles in the excessive production of hepatic Th1 cytokines in NAFLD. In addition, liver innate immune cells participate in the pathogenesis of NAFLD in other ways. For example, activated KCs can generate reactive oxygen species, which induce liver injury. This review will focus primarily on the possible effect and mechanism of KCs, NKT cells and NK cells in the development of NAFLD.展开更多
Atherosclerosis is a chronic inflammatory disease arising from lipids, specifically low-density lipoproteins, and leukocytes. Following the activation of endothelium with the expression of adhesion molecules and monoc...Atherosclerosis is a chronic inflammatory disease arising from lipids, specifically low-density lipoproteins, and leukocytes. Following the activation of endothelium with the expression of adhesion molecules and monocytes, inflammatory cytokines from macrophages, and plasmacytoid dendritic cells, high levels of interferon(IFN)-α and β are generated upon the activation of tolllike receptor-9, and T-cells, especially the ones with Th1 profile, produce pro-inflammatory mediators such as IFN-γ and upregulate macrophages to adhere to the endothelium and migrate into the intima. This review presents an exhaustive account for the role of immunecells in the atherosclerosis.展开更多
The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.Howeve...The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.展开更多
Lizards are key amniote models for studying organ regeneration. During tail regeneration in lizards, blastemas contain sparse granulocytes, macrophages, and lymphocytes among the prevalent mesenchymal cells. Using tra...Lizards are key amniote models for studying organ regeneration. During tail regeneration in lizards, blastemas contain sparse granulocytes, macrophages, and lymphocytes among the prevalent mesenchymal cells. Using transmission electron microscopy to examine scarring blastemas after third and fourth sequential tail amputations, the number of granulocytes, macrophages, and lymphocytes increased at 3-4 weeks in comparison to the first regeneration. An increase in granulocytes and agranulocytes also occurred within a week after blastema cauterization during the process of scarring Blood at the third and fourth regeneration also showed a significant increase in white blood cells compared with that under normal conditions and at the first regeneration. The extracellular matrix of the scarring blastema, especially after cauterization, was denser than that in the normal blastema and numerous white blood cells and fibroblasts were surrounded by electron-pale, fine fibrinoid material mixed with variable collagen fibrils. In addition to previous studies, the present observations support the hypothesis that an increase in inflammation and immune reactions determine scarring rather than regeneration. These new findings verify that an immune reaction against mesenchymal and epidermal cells of the regenerative blastema is one of the main causes for the failure of organ regeneration in amniotes.展开更多
Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatm...Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.展开更多
BACKGROUND Immune cells,including neutrophils,natural killer(NK)cells,T cells,NKT cells and macrophages,participate in the progression of acute liver injury and hepatic recovery.To date,there has been no systematic st...BACKGROUND Immune cells,including neutrophils,natural killer(NK)cells,T cells,NKT cells and macrophages,participate in the progression of acute liver injury and hepatic recovery.To date,there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time,and to study the relationship between the changes in leukocyte cellderived chemotaxin 2(LECT2)and the infiltration of several immune cells.METHODS Carbon tetrachloride-and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively.The quantitative changes in various immune cells were monitored at different time points.Serum samples were collected,and liver tissues were harvested.Ly6G,CD161,CD4,CD8 and F4/80 staining were used to indicate neutrophils,NK/NKT cells,CD4^(+)T cells,CD8^(+)T cells and macrophages,respectively.Lect2-KO mice were used to detect the function of LECT2.RESULTS During the injury and repair process,different types of immune cells began to increase,reached their peaks and fell into decline at different time points.Furthermore,when the serum alanine transaminase(ALT)and aspartate transaminase(AST)indices reverted to normal levels 7 d after the injury,the infiltration of immune cells still existed even 14 d after the injury,showing an obvious lag effect.We found that the expression of LECT2 was upregulated in acute liver injury mouse models,and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice.Compared with wild-type mice,Lect2-KO mice had different immune cell infiltration.CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair.LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.展开更多
Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immun...Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.展开更多
Objective:The aim of this study was to identify hub genes associated with immune cell infiltration in breast cancer through bioinformatic analyses of multiple datasets.Methods:Nonparametric(NOISeq)and robust rank aggr...Objective:The aim of this study was to identify hub genes associated with immune cell infiltration in breast cancer through bioinformatic analyses of multiple datasets.Methods:Nonparametric(NOISeq)and robust rank aggregation-ranked parametric(EdgeR)methods were used to assess robust differentially expressed genes across multiple datasets.Protein-protein interaction network,GO,KEGG enrichment,and subnetwork analyses were performed to identify immune-associated hub genes in breast cancer.Immune cell infiltration was evaluated with the CIBERSORT,XCELL,and TIMER methods.The association between the hub gene-based risk signature and survival was determined through Kaplan–Meier survival analysis,multivariate Cox analysis,and a nomogram with external verification.Results:We identified 163 robust differentially expressed genes in breast cancer through applying both nonparametric and parametric methods to multiple GEO(n=2,212)and TCGA(n=1,045)datasets.Integrated bioinformatic analyses further identified 10 hub genes:CXCL10,CXCL9,CXCL11,SPP1,POSTN,MMP9,DPT,COL1A1,ADAMDEC1,and RGS1.The 10 hub-gene-based risk signature significantly correlated with the prognosis of patients with breast cancer.Moreover,these hub genes were strongly associated with the extent of infiltration of CD4+T cells,CD8+T cells,neutrophils,macrophages,and myeloid dendritic cells into breast tumors.Conclusions:Integrated analyses of multiple databases led to the discovery of 10 robust hub genes that together may serve as a risk factor characteristic of the immune microenvironment in breast cancer.展开更多
Regulator of G-protein Signaling 10 (Rgsl0) plays an important function in osteoclast differentiation. However, the role of Rgsl0 in immune cells and inflammatory responses, which activate osteoclasts in inflam- mat...Regulator of G-protein Signaling 10 (Rgsl0) plays an important function in osteoclast differentiation. However, the role of Rgsl0 in immune cells and inflammatory responses, which activate osteoclasts in inflam- matory lesions, such as bacteria-induced periodontal disease lesions, remains largely unknown. In this study, we used an adeno-associated virus (AAV-) mediated RNAi (AAV-shRNA-Rgs10) knockdown approach to study Rgsl0's function in immune cells and osteoclasts in bacteria-induced inflammatory lesions in a mouse model of periodontal disease. We found that AAV-shRNA-Rgs10 mediated Rgs10 knockdown impaired osteoclastogenesis and osteoclast-mediated bone resorption, in vitro and in vivo. Interestingly, local injection of AAV-shRNA-Rgs10 into the periodontal tissues in the bacteria-induced inflammatory lesion greatly decreased the number of dendritic cells, T-cells and osteoclasts, and protected the periodontal tissues from local inflammatory damage and bone destruction. Importantly, AAV-mediated Rgs10 knockdown also reduced local expression of osteoclast markers and pro-inflammatory cytokines. Our results demonstrate that AAV- shRNA-Rgs10 knockdown in periodontal disease tissues can prevent bone resorption and inflammation simultaneously. Our data indicate that Rgsl0 may regulate dendritic cell proliferation and maturation, as well as the subsequent stimulation of T-cell proliferation and maturation, and osteoclast differentiation and acti- vation. Our study suggests that AAV-shRNA-Rgs10 can be useful as a therapeutic treatment of periodontal disease.展开更多
基金supported by grants from National Natural Science Foundation of China (No. 30700799, 81172803)Doctoral Fund of Ministry of Education of China (No. 20070487119)Natural Science Foundation of Hubei Province (No. 2007AD A201)
文摘T cell immunoglobulin and mucin domain 3 (Tim-3) is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to identify the relationship between Tim-3 expression and post-burn T cells immune suppression, C57BL/6 mice were subjected to burn injury or sham injury, and the liver and spleen were harvested at the day 1 after operation. The expression level of Tim-3 on hepatic or splenic T cells and the functional properties of Tim-3+ T cells were evaluated. It was found burn injury induced dramatically elevated Tim-3 expression on both hepatic and splenic CD4+ and CD8+ T cells in contrast with the post-burn depletion of T cells. Furthermore, Tim-3 expression was correlated with the suppressive phenotype of T cells following burn injury, including increased expression of anti-inflammatory cytokine IL-10, decreased expression of pro-inflammatory cytokines IFN-γ and TNF-α, reduced T cell proliferation and elevated co-expression of Tim-3 and PD-1. Moreover, Tim-3+ T cells subsets were more prone to spontaneous apoptosis than Tim-3- T cells subsets. Our findings reinforce the idea that the up-regulated expression of Tim-3 on T cells after burn injury plays an important role in the development and maintenance of burn-induced T cell immune suppression.
基金partially supported by the Natural Science Foundation of Zhejiang Province(Award number:D21C170001)the National Natural Science Foundation of China(Award number:31973000)。
文摘Background Four-chambered stomach including the forestomachs(rumen,reticulum,and omasum)and abomasum allows ruminants convert plant fiber into high-quality animal products.The early development of this four-chambered stomach is crucial for the health and well-being of young ruminants,especially the immune development.However,the dynamics of immune development are poorly understood.Results We investigated the early gene expression patterns across the four-chambered stomach in Hu sheep,at 5,10,15,and 25 days of age.We found that forestomachs share similar gene expression patterns,all four stomachs underwent widespread activation of both innate and adaptive immune responses from d 5 to 25,whereas the metabolic function were significantly downregulated with age.We constructed a cell landscape of the four-chambered stomach using single-cell sequencing.Integrating transcriptomic and single-cell transcriptomic analyses revealed that the immune-associated module hub genes were highly expressed in T cells,monocytes and macrophages,as well as the defense-associated module hub genes were highly expressed in endothelial cells in the four-stomach tissues.Moreover,the non-immune cells such as epithelial cells play key roles in immune maturation.Cell communication analysis predicted that in addition to immune cells,non-immune cells recruit immune cells through macrophage migration inhibitory factor signaling in the forestomachs.Conclusions Our results demonstrate that the immune and defense responses of four stomachs are quickly developing with age in lamb's early life.We also identified the gene expression patterns and functional cells associated with immune development.Additionally,we identified some key receptors and signaling involved in immune regulation.These results help to understand the early life immune development at single-cell resolution,which has implications to develop nutritional manipulation and health management strategies based on specific targets including key receptors and signaling pathways.
基金Supported by National Natural Foundation of China,No.821742232019 Chinese and Western Medicine Clinical Collaborative Capacity Building Project for Major Difficult Diseases,No.2019-ZX-005。
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most common malignancies worldwide,and its development comprises a multistep process from intraepithelial neoplasia(IN)to carcinoma(CA).However,the critical regulators and underlying molecular mechanisms remain largely unknown.AIM To explore the genes and infiltrating immune cells in the microenvironment that are associated with the multistage progression of ESCC to facilitate diagnosis and early intervention.METHODS A mouse model mimicking the multistage development of ESCC was established by providing warter containing 4-nitroquinoline 1-oxide(4NQO)to C57BL/6 mice.Moreover,we established a control group without 4NQO treatment of mice.Then,transcriptome sequencing was performed for esophageal tissues from patients with different pathological statuses,including low-grade IN(LGIN),high-grade IN(HGIN),and CA,and controlled normal tissue(NOR)samples.Differentially expressed genes(DEGs)were identified in the LGIN,HGIN,and CA groups,and the biological functions of the DEGs were analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The CIBERSORT algorithm was used to detect the pattern of immune cell infilt-ration.Immunohistochemistry(IHC)was also conducted to validate our results.Finally,the Luminex multiplex cytokine analysis was utilized to measure the serum cytokine levels in the mice.RESULTS Compared with those in the NOR group,a total of 681541,and 840 DEGs were obtained in the LGIN,HGIN,and CA groups,respectively.Using the intersection of the three sets of DEGs,we identified 86 genes as key genes involved in the development of ESCC.Enrichment analysis revealed that these genes were enriched mainly in the keratinization,epidermal cell differentiation,and interleukin(IL)-17 signaling pathways.CIBERSORT analysis revealed that,compared with those in the NOR group,M0 and M1 macrophages in the 4NQO group showed stronger infiltration,which was validated by IHC.Serum cytokine analysis revealed that,compared with those in the NOR group,IL-1βand IL-6 were upregulated,while IL-10 was downregulated in the LGIN,HGIN,and CA groups.Moreover,the expression of the representative key genes,such as S100a8 and Krt6b,was verified in external human samples,and the results of immunohistochemical staining were consistent with the findings in mice.CONCLUSION We identified a set of key genes represented by S100a8 and Krt6b and investigated their potential biological functions.In addition,we found that macrophage infiltration and abnormal alterations in the levels of inflam-mation-associated cytokines,such as IL-1β,IL-6,and IL-10,in the peripheral blood may be closely associated with the development of ESCC.
基金supported by the National Key R&D Program of China(Grant No.2022YFA1103300)the National Natural Science Foundation of China(Grant No.82020108004)+3 种基金the Natural Science Foundation of Chongqing Innovation Group Science Program(Grant No.cstc2021jcyjcxttX0001)the Natural Science Foundation of Chongqing(Grant No.CSTB2022NSCQ-MSX1060)the Special Project for Talent Construction in Xinqiao Hospital(Grant No.2022XKRC001)the National College Student Innovation and Entrepreneurship Training Program(Grant No.202190035001).
文摘Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation(allo-HSCT)has been widely implemented to treat hematologic malignancies.However,graft-versus-host disease(GVHD)and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life.In addition,GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions(DLIs)and chimeric antigen receptor(CAR)T-cell therapy.Because of the special immune tolerance characteristics and anti-tumor ability of universal immune cells,universal immune cell therapy may strongly reduce GVHD,while simultaneously reducing tumor burden.Nevertheless,widespread application of universal immune cell therapy is mainly restricted by poor expansion and persistence efficacy.Many strategies have been applied to improve universal immune cell proliferation and persistence efficacy,including the use of universal cell lines,signaling regulation and CAR technology.In this review we have summarized current advances in universal immune cell therapy for hematologic malignancies with a discussion of future perspectives.
基金funded by the Sichuan Natural Science Foundation(No.2022NSFSCO654)the Radiation Oncology Key Laboratory of Sichuan Province Open Fund(No.2020FSZLX-03)the UESTC-Sichuan Cancer Hospital 2021 Medical-Engineering Oncology Innovation Fund(No.ZYGX2021YGCX013).
文摘Tanshinone IIA,one of the main ingredients of Danshen,is used to treat hepatocellular carcinoma(HCC).However,potential targets of the molecule in the therapy of HCC are unknown.Methods:In this study,we collected the tanshinone IIA targets from public databases for investigation.We screened differentially expressed genes(DEGs)across HCC and normal tissues using mRNA expression profiles from The Cancer Genome Atlas(TCGA).Univariate Cox regression analysis and least absolute shrinkage and selection operator(LASSO)Cox regression models were used to identify and construct the prognostic gene signature.Results:Finally,we discovered common genes across tanshinone IIA targets and HCC DEGs.We reported Fatty acid binding protein-6(FABP6),Polo-like Kinase 1(PLK1),deoxythymidylate kinase(DTYMK),Uridine Cytidine Kinase 2(UCK2),Enhancer of Zeste Homolog 2(EZH2),and Cytochrome P4502C9(CYP2C9)as components of a gene signature.The six-gene signature’s prognostic ability was evaluated using the Kaplan-Meier curve,time-dependent receiver operating characteristic(ROC),multivariate Cox regression analysis,and the nomogram.The mRNA level and protein expression of UCK2 were experimentally validated after treatment with different concentrations of tanshinone IIA in HEPG2 cells.CIBERSORTx,TIMER2.0,and GEPIA2 tools were employed to explore the relationship between the prognostic signature and immune cell infiltration.Conclusion:We established a six-gene signature as a reliable model with significant therapeutic possibility for prognosis and overall survival estimation in HCC patients,which might also benefit medical decision-making for appropriate treatment.
基金supported by the National Key Research and Development Program of China(2017YFA0700403),the Hainan University Scientic Research Foundation(KYQD(ZR)20078)the National Natural Science Foundation of China(81901691)。
文摘As the largest internal organ of the human body,the liver has an extremely complex vascularnetwork and multiple types of immune cells.It plays an important role in blood circulation,material metabolism,and immune response.Optical imaging is an effective tool for studying finevascular structure and immunocyte distribution of the liver.Here,we provide an overview of thestructure and composition of liver vessels,the threedimensional(3D)imaging of the liver,andthe spatial distribution and immune function of various cell components of the liver.Especially,we emphasize the 3D imaging methods for visualizing fine structure in the liver.Finally,wesummarize and prospect the development of 3D imaging of liver vesels and immune cells.
文摘We have found that the expression of ring finger and WD repeat domain 3(RFWD3)is significantly higher in unpaired and paired hepatocellular carcinoma(HCC)tissues than in normal tissues.Moreover,this expression has a significant correlation with the infiltration level of 14 immune cell types and when the detected RFWD3 expression levels were grouped as high and low,a prominent difference was revealed for overall survival,disease-specific survival,and progression-free interval.Through statistical analysis(univariate Cox),we were also able to identify RFWD3 as an independent prognostic element for HCC,with RFWD3 having an ability to accurately predict HCC prognosis(area under the curve of 0.863).Finally,we have generated prognostic nomograms for probabilities of 1-,3-and 5-year overall survival in HCC via integrating the factors of age,pathologic stage,alpha-fetoprotein level,and RFWD3 expression.
基金Beijing Hope Run Special Fund of Cancer Foundation of China,No.LC2020L05.
文摘BACKGROUND Spindle and kinetochore-associated complex subunit 3(SKA3)is a malignancyassociated gene that plays a critical role in the regulation of chromosome separation and cell division.However,the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma(HCC)has not been fully elucidated.AIM To investigate the molecular mechanisms underlying the role of SKA3 in HCC.METHODS SKA3 expression,clinicopathological,and survival analyses were performed using multiple public database platforms,and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples.Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC.Furthermore,the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis(ssGSEA)algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC.The response to chemotherapeutic drugs was evaluated by the R package“pRRophetic”.RESULTS We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC.Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival.GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair.Moreover,patients with high SKA3 expression had significantly decreased ratios of CD8+T cells,natural killer cells,and dendritic cells.Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib,sunitinib,paclitaxel,doxorubicin,gemcitabine,and vx-680.CONCLUSION High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC.SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.
基金supported by grants from the Major Program of National Key Research and Development Project,Nos.2020YFA0112600(to ZH)the National Natural Science Foundation of China,No.82171270(to ZL)+5 种基金Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People’s Republic of China,No.2020-0103-3-1(to ZL)the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)CAMS Innovation Fund for Medical Sciences,No.2019-I2M-5-029(to YW)Shanghai Engineering Research Center of Stem Cells Translational Medicine,No.20DZ2255100(to ZH).
文摘Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.
基金the Domestic First-class Construction Disciplines of the Hunan University of Chinese MedicinePostgraduate Research Innovation Program of Hunan Province,No.CX20220771Clinical MedTech Innovation Project of Hunan Province,No.2021SK51415.
文摘BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.
文摘Background: A major cause of cancer death worldwide is bladder cancer, which is the most common malignant tumor of the urinary tract. PAEP is a member of the kernel lipocalin superfamily whose members share relatively low sequence similarity but have highly conserved exon/intron structure and three-dimensional protein folding. Most lipocalins are clustered on the long arm of chromosome 9. The purpose of this study was to clarify the correlation between PAEP expression level and bladder cancer. Methods: In the TCGA database, we obtained clinical and RNA sequencing data of 431 BLCA patients, including 412 BLCA tissues and 19 normal bladder tissues in the study. Analyses of bioinformatics were conducted in this study to determine the role of PAEP in bladder cancer. A quantitative real-time PCR method was used to quantitate the gene expression profile. Additionally, the effect of PAEP on tumor immune infiltration and prognosis was analyzed. Results: PAEP was a poor prognostic biomarker of bladder cancer because it was significantly upregulated. bladder cancer patients with higher PAEP expression had poor outcomes. An AUC of 0.780 was calculated from the area under the ROC curve. PAEP was associated with T stage, pathologic stage, Histologic grade and Subtype of bladder cancer patients, and served as an independent predictor of overall survival in bladder cancer patients. Functional enrichment analysis revealed PAEP was obviously enriched in pathways connected with carcinogenesis and immunosuppression. The expression of PAEP was significantly associated with tumor immune cells and immune checkpoints according to ssGSEA and Spearman correlation analysis. Conclusions: In this study, we screened and detected a mRNA, PAEP is a prognostic and immune-related biomarker in BLCA, which may contribute to the early diagnosis and treatment of BLCA.
基金Supported by Beijing Municipal Laboratory for Liver Protection and Regulation of Regeneration, Beijing, China
文摘Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding the pathogenesis of NAFLD is of great clinical importance and is critical for the prevention and treatment of the disease. Although the "two-hit hypothesis" is generally accepted, the exact pathogenesis of NAFLD has not been clearly established. The liver is an important innate immune organ with large numbers of innate immune cells, including Kupffer cells (KCs), natural killer T (NKT) cells and natural killer (NK) cells. Recent data show that an imbalance in liver cytokines may be implicated in the development of fatty liver disease. For example, Th1 cytokine excess may be a common pathogenic mechanism for hepatic insulin resistance and NASH. Innate immune cells in the liver play important roles in the excessive production of hepatic Th1 cytokines in NAFLD. In addition, liver innate immune cells participate in the pathogenesis of NAFLD in other ways. For example, activated KCs can generate reactive oxygen species, which induce liver injury. This review will focus primarily on the possible effect and mechanism of KCs, NKT cells and NK cells in the development of NAFLD.
文摘Atherosclerosis is a chronic inflammatory disease arising from lipids, specifically low-density lipoproteins, and leukocytes. Following the activation of endothelium with the expression of adhesion molecules and monocytes, inflammatory cytokines from macrophages, and plasmacytoid dendritic cells, high levels of interferon(IFN)-α and β are generated upon the activation of tolllike receptor-9, and T-cells, especially the ones with Th1 profile, produce pro-inflammatory mediators such as IFN-γ and upregulate macrophages to adhere to the endothelium and migrate into the intima. This review presents an exhaustive account for the role of immunecells in the atherosclerosis.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81974416 and 81872166)the Key Project of Tianjin Health Industry(Grant No.15KG145).
文摘The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.
文摘Lizards are key amniote models for studying organ regeneration. During tail regeneration in lizards, blastemas contain sparse granulocytes, macrophages, and lymphocytes among the prevalent mesenchymal cells. Using transmission electron microscopy to examine scarring blastemas after third and fourth sequential tail amputations, the number of granulocytes, macrophages, and lymphocytes increased at 3-4 weeks in comparison to the first regeneration. An increase in granulocytes and agranulocytes also occurred within a week after blastema cauterization during the process of scarring Blood at the third and fourth regeneration also showed a significant increase in white blood cells compared with that under normal conditions and at the first regeneration. The extracellular matrix of the scarring blastema, especially after cauterization, was denser than that in the normal blastema and numerous white blood cells and fibroblasts were surrounded by electron-pale, fine fibrinoid material mixed with variable collagen fibrils. In addition to previous studies, the present observations support the hypothesis that an increase in inflammation and immune reactions determine scarring rather than regeneration. These new findings verify that an immune reaction against mesenchymal and epidermal cells of the regenerative blastema is one of the main causes for the failure of organ regeneration in amniotes.
基金This work was supported by the National Key Technologies R&D Program(Grant No.2015BAI12B12)the National Key R&D Program(Grant No.2018YFC1313400)+2 种基金grants from the National Natural Science Foundation of China(Grant Nos.81802873 and 81672697)the Natural Science Foundation of Tianjin(Grant No.18JCQNJC81300)the Tianjin Municipal Education Commission Program(Grant No.2017KJ197).
文摘Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.
基金Supported by the National Key R&D Program of ChinaNo. 2018YFA0108200 and No. 2018YFC1106400+5 种基金the National Natural Science Foundation of ChinaNo. 31972926, No. 32000607, No. 82270645 and No. 92068206Guangdong Basic and Applied Basic Research FoundationNo. 2020A1515111111 and No. 2019A1515110145China Postdoctoral Science FoundationNo. 2019M660205
文摘BACKGROUND Immune cells,including neutrophils,natural killer(NK)cells,T cells,NKT cells and macrophages,participate in the progression of acute liver injury and hepatic recovery.To date,there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time,and to study the relationship between the changes in leukocyte cellderived chemotaxin 2(LECT2)and the infiltration of several immune cells.METHODS Carbon tetrachloride-and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively.The quantitative changes in various immune cells were monitored at different time points.Serum samples were collected,and liver tissues were harvested.Ly6G,CD161,CD4,CD8 and F4/80 staining were used to indicate neutrophils,NK/NKT cells,CD4^(+)T cells,CD8^(+)T cells and macrophages,respectively.Lect2-KO mice were used to detect the function of LECT2.RESULTS During the injury and repair process,different types of immune cells began to increase,reached their peaks and fell into decline at different time points.Furthermore,when the serum alanine transaminase(ALT)and aspartate transaminase(AST)indices reverted to normal levels 7 d after the injury,the infiltration of immune cells still existed even 14 d after the injury,showing an obvious lag effect.We found that the expression of LECT2 was upregulated in acute liver injury mouse models,and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice.Compared with wild-type mice,Lect2-KO mice had different immune cell infiltration.CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair.LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.
基金supported by grants from the National Natural Science Foundation of China(81971495 and 91442117)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-035)+2 种基金the National Science Foundation of Jiangsu Province(BRA2017533 and BK20191490)the State Key Laboratory of Reproductive Medicine(SKLRM-K202001)the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials。
文摘Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81874167 and 82073064).
文摘Objective:The aim of this study was to identify hub genes associated with immune cell infiltration in breast cancer through bioinformatic analyses of multiple datasets.Methods:Nonparametric(NOISeq)and robust rank aggregation-ranked parametric(EdgeR)methods were used to assess robust differentially expressed genes across multiple datasets.Protein-protein interaction network,GO,KEGG enrichment,and subnetwork analyses were performed to identify immune-associated hub genes in breast cancer.Immune cell infiltration was evaluated with the CIBERSORT,XCELL,and TIMER methods.The association between the hub gene-based risk signature and survival was determined through Kaplan–Meier survival analysis,multivariate Cox analysis,and a nomogram with external verification.Results:We identified 163 robust differentially expressed genes in breast cancer through applying both nonparametric and parametric methods to multiple GEO(n=2,212)and TCGA(n=1,045)datasets.Integrated bioinformatic analyses further identified 10 hub genes:CXCL10,CXCL9,CXCL11,SPP1,POSTN,MMP9,DPT,COL1A1,ADAMDEC1,and RGS1.The 10 hub-gene-based risk signature significantly correlated with the prognosis of patients with breast cancer.Moreover,these hub genes were strongly associated with the extent of infiltration of CD4+T cells,CD8+T cells,neutrophils,macrophages,and myeloid dendritic cells into breast tumors.Conclusions:Integrated analyses of multiple databases led to the discovery of 10 robust hub genes that together may serve as a risk factor characteristic of the immune microenvironment in breast cancer.
基金supported by NIH grants RC1DE-020533 (Y.P.L.) and AR-055307 (Y.P.L.)
文摘Regulator of G-protein Signaling 10 (Rgsl0) plays an important function in osteoclast differentiation. However, the role of Rgsl0 in immune cells and inflammatory responses, which activate osteoclasts in inflam- matory lesions, such as bacteria-induced periodontal disease lesions, remains largely unknown. In this study, we used an adeno-associated virus (AAV-) mediated RNAi (AAV-shRNA-Rgs10) knockdown approach to study Rgsl0's function in immune cells and osteoclasts in bacteria-induced inflammatory lesions in a mouse model of periodontal disease. We found that AAV-shRNA-Rgs10 mediated Rgs10 knockdown impaired osteoclastogenesis and osteoclast-mediated bone resorption, in vitro and in vivo. Interestingly, local injection of AAV-shRNA-Rgs10 into the periodontal tissues in the bacteria-induced inflammatory lesion greatly decreased the number of dendritic cells, T-cells and osteoclasts, and protected the periodontal tissues from local inflammatory damage and bone destruction. Importantly, AAV-mediated Rgs10 knockdown also reduced local expression of osteoclast markers and pro-inflammatory cytokines. Our results demonstrate that AAV- shRNA-Rgs10 knockdown in periodontal disease tissues can prevent bone resorption and inflammation simultaneously. Our data indicate that Rgsl0 may regulate dendritic cell proliferation and maturation, as well as the subsequent stimulation of T-cell proliferation and maturation, and osteoclast differentiation and acti- vation. Our study suggests that AAV-shRNA-Rgs10 can be useful as a therapeutic treatment of periodontal disease.