Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellu...Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms.Histones,von Willebrand factor,fibrin,and many other factors participate in the interplay between inflammation and thrombosis.Neuroimmunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases,providing cutting-edge insights into post-neurotrauma thrombotic events.The blood-brain barrier defends the brain and spinal cord against external assaults,and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases.Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis,but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis,and identified modulators of neuro-immunothrombosis.However,these neurological diseases occur in blood vessels,and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury.This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.展开更多
Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been...Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan–Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADPribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.展开更多
The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction b...The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune–bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNAsequencing analysis on mouse periodontal lesions and showed that neutrophil–osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.展开更多
Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide ...Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.展开更多
BACKGROUND Circulating tumor cell(CTC)count and neutrophil-to-lymphocyte ratio(NLR)are both closely associated with the prognosis of hepatocellular carcinoma(HCC).AIM To investigate the prognostic value of combining t...BACKGROUND Circulating tumor cell(CTC)count and neutrophil-to-lymphocyte ratio(NLR)are both closely associated with the prognosis of hepatocellular carcinoma(HCC).AIM To investigate the prognostic value of combining these two indicators in HCC.METHODS Clinical data were collected from patients with advanced HCC who received im-mune therapy combined with targeted therapy at the Department of Oncology,the Affiliated Hospital of Southwest Medical University,Sichuan,China,from 2021 to 2023.The optimal cutoff values for CTC programmed death-ligand 1(PD-L1)(+)>1 or CTC PD-L1(+)≤1 and NLR>3.89 or NLR≤3.89 were evaluated using X-Tile software.Patients were categorized into three groups based on CTC PD-L1(+)counts and NLR:CTC-NLR(0),CTC-NLR(1),and CTC-NLR(2).The relationship between CTC-NLR and clinical variables as well as survival rates was assessed.RESULTS Patients with high CTC PD-L1(+)expression or NLR at baseline had shorter median progression-free survival(m-PFS)and median overall survival(mOS)than those with low levels of CTC PD-L1(+)or NLR(P<0.001).Mean-while,patients in the CTC-NLR(2)group showed a significant decrease in mPFS and mOS.Cox regression analysis revealed that alpha-fetoprotein(AFP),CTC PD-L1(+),and CTC-NLR were independent predictors of OS.The time-dependent receiver operating characteristic curve showed that the area under the curve of CTC-NLR at 12 months(0.821)and 18 months(0.821)was superior to that of AFP and CTC PD-L1(+).CONCLUSION HCC patients with high CTC PD-L1(+)or NLR expression tend to exhibit poor prognosis,and a high baseline CTC-NLR score may indicate low survival.CTC-NLR may serve as an effective prognostic indicator for patients with advanced HCC receiving immunotherapy combined with targeted therapy.展开更多
Rheumatoid arthritis(RA)is a prevalent autoimmune disease whose main features include chronic synovial inflammation,bone destruction,and joint degeneration.Neutrophils are often considered to be the first responders t...Rheumatoid arthritis(RA)is a prevalent autoimmune disease whose main features include chronic synovial inflammation,bone destruction,and joint degeneration.Neutrophils are often considered to be the first responders to inflammation and are a key presence in the inflammatory milieu of RA.Neutrophil extracellular traps(NETs),a meshwork of DNA-histone complexes and proteins released by activated neutrophils,are widely involved in the pathophysiology of autoimmune diseases,especially RA,in addition to playing a key role in the neutrophil innate immune response.NETs have been found to be an important source of citrullinated autoantigen antibodies and inflammatory factor release,which can activate RA synovial fibroblasts(FLS)and cause joint damage.This article reviews the role of NETs in the pathophysiology of RA,demonstrating the application of multiple molecules with various therapies,with a view to informing the discovery and development of novel biomarkers and therapeutic targets for RA.展开更多
Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and ...Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.展开更多
Objective:To explore correlation of neutrophil-to-lymphocyte ratio(NLR)to severity of coronary artery disease(CAD)and in-hospital clinical outcomes in patients with acute coronary syndrome(ACS).Methods:In this prospec...Objective:To explore correlation of neutrophil-to-lymphocyte ratio(NLR)to severity of coronary artery disease(CAD)and in-hospital clinical outcomes in patients with acute coronary syndrome(ACS).Methods:In this prospective and observational study,we recruited 500 patients with ACS.For all the eligible patients,demographic details were collected,and laboratory parameters were evaluated.The CAD severity was evaluated in terms of the number of involved vessels.The NLR was calculated based on neutrophils and lymphocytes and the correlation of various risk factors and severity and outcome of CAD was performed.Results:77.2%of Patients was male,and 52%of the patients aged between 55-70 years.Based on the type of ACS,396 out of 500 patients had ST-elevation myocardial infarction.An ascending trend in the white blood cell levels and NLR value was noted as the severity of the ACS increased and the highest white blood cell levels and NLR was noted among classⅣpatients.The mean NLR value among the non-survivors were higher compared to the survivors(9.52±5.72 vs.4.76±2.36;P<0.01).Receiver operating curve showed that the cut-off NLR value was 5.76 with a sensitivity of 75.0%and a specificity of 77.3%.Conclusions:The NLR can be used as an independent prognostic marker in ACS.An elevated NLR value serves as a reliable predictor for short-term complications,notably in-hospital mortality.展开更多
[Objectives]This study was conducted to explore the relationship between neutrophil percentage-to-albumin ratio(NPAR)and coronary heart disease complicated with diabetes.[Methods]A total of 603 patients with coronary ...[Objectives]This study was conducted to explore the relationship between neutrophil percentage-to-albumin ratio(NPAR)and coronary heart disease complicated with diabetes.[Methods]A total of 603 patients with coronary heart disease who underwent coronary angiography in Pingquan County Hospital from January,2023 to December,2023 and met the inclusion criteria were included as the research object.All the patients were divided into a coronary heart disease complicated with diabetes group(CAD+T2DM group)(n=298 cases)and a control group(CAD group)(n=305 cases),according to patients medical history,heart color ultrasound and biochemical test results.The clinical data,biochemical test results and coronary artery imaging data of patients were recorded,and the Gensini score was calculated.The neutrophil percentage(NEUT%)and albumin count were determined to calculate NPAR.[Results]The NPAR value of the coronary heart disease complicated with diabetes mellitus group was(1.6±0.42),which was significantly higher than that of the control group(1.47±0.49),and the difference was statistically significant(P<0.05).The area under the ROC curve was 0.619(95%CI:0.591-0.675,P<0.05),and the prediction of coronary heart disease complicated with diabetes using NPAR showed a Youden index of 0.31,a sensitivity of 60.4%,a specificity of 40.3%,and a best cut-off score of 1.4506.[Conclusions]The neutrophil percentage-to-albumin ratio(NPAR)is closely related to coronary heart disease complicated with diabetes mellitus,and NPAR has clinical application value in the diagnosis of coronary heart disease complicated with diabetes mellitus.展开更多
Neutrophil elastase(NE),a major protease in the primary granules of neutrophils,is involved in microbicidal activity.NE is an important factor promoting inflammation,has bactericidal effects,and shortens the inflammat...Neutrophil elastase(NE),a major protease in the primary granules of neutrophils,is involved in microbicidal activity.NE is an important factor promoting inflammation,has bactericidal effects,and shortens the inflammatory process.NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling.However,NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction.Additionally,it plays a complex role in various physiological processes and mediates several diseases.Sivelestat,a specific NE inhibitor,has strong potential for clinical application,particularly in the treatment of coronavirus disease 2019(COVID-19).This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.展开更多
After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been full...After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury(sub-acute phase), genome-wide transcriptomic data showed that interleukin 17 A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17 A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17 A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17 A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17 A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17 A may be a promising therapeutic target for traumatic brain injury.展开更多
Primary and metastatic lung cancers are malignant lung tumors each with of which has a different pathogenesis,although both threaten patient lives.Tumor development and progression involve communication between tumor ...Primary and metastatic lung cancers are malignant lung tumors each with of which has a different pathogenesis,although both threaten patient lives.Tumor development and progression involve communication between tumor cells and the host microenvironment.Neutrophils are the most abundant immune cells in the tumor microenvironment(TME);they participate in the generation of an inflammatory milieu and influence patient survival through their anti-and pro-tumor abilities.Neutrophils can be classified into various categories according to different criteria;frequent categories include N1 antitumor neutrophils and N2 immunosuppressive neutrophils.The antitumor effects of neutrophils are reported to be mediated through a combination of reactive oxygen species,tumor necrosis factor-related apoptosis-inducing ligand,and receptor for advanced glycation end-products–cathepsin G association,as well as the regulation of the activities of other immune cells.There have also been reports that neutrophils can function as tumor promoters that contribute to lung cancer progression and metastasis by influencing processes including carcinogenesis,angiogenesis,cancer cell proliferation,and invasion ability,as well as having similar roles in the lung metastasis of other cancers.The rapid development of nanotechnology has provided new strategies for cancer treatment targeting neutrophils.展开更多
Objective The hypersensitivity of the kidney makes it susceptible to hypoxia injury.The involvement of neutrophil extracellular traps(NETs)in renal injury resulting from hypobaric hypoxia(HH)has not been reported.In t...Objective The hypersensitivity of the kidney makes it susceptible to hypoxia injury.The involvement of neutrophil extracellular traps(NETs)in renal injury resulting from hypobaric hypoxia(HH)has not been reported.In this study,we aimed to investigate the expression of NETs in renal injury induced by HH and the possible underlying mechanism.Methods A total of 24 SD male rats were divided into three groups(n=8 each):normal control group,hypoxia group and hypoxia+pyrrolidine dithiocarbamate(PDTC)group.Rats in hypoxia group and hypoxia+PDTC group were placed in animal chambers with HH which was caused by simulating the altitude at 7000 meters(oxygen partial pressure about 6.9 kPa)for 7 days.PDTC was administered at a dose of 100 mg/kg intraperitoneally once daily for 7 days.Pathological changes of the rat renal tissues were observed under a light microscope;the levels of serum creatinine(SCr),blood urea nitrogen(BUN),cell-free DNA(cf-DNA)and reactive oxygen species(ROS)were measured;the expression levels of myeloperoxidase(MPO),citrullinated histone H3(cit-H3),B-cell lymphoma 2(Bcl-2),Bax,nuclear factor kappa B(NF-κB)p65 and phospho-NF-κB p65(p-NF-κB p65)in rat renal tissues were detected by qRT-qPCR and Western blotting;the localization of NF-κB p65 expression in rat renal tissues was observed by immunofluorescence staining and the expression changes of NETs in rat renal tissues were detected by multiplex fluorescence immunohistochemical staining.Results After hypoxia,the expression of NF-κB protein in renal tissues was significantly increased,the levels of SCr,BUN,cf-DNA and ROS in serum were significantly increased,the formation of NETs in renal tissues was significantly increased,and a large number of tubular dilatation and lymphocyte infiltration were observed in renal tissues.When PDTC was used to inhibit NF-κB activation,NETs formation in renal tissue was significantly decreased,the expression level of Bcl-2 in renal tissues was significantly increased,the expression level of Bax was significantly decreased,and renal injury was significantly alleviated.Conclusion HH induces the formation of NETs through the NF-κB signaling pathway,and it promotes apoptosis and aggravates renal injury by decreasing Bcl-2 and increasing Bax expression.展开更多
Background:Mammary health is important for transition dairy cows and has been well recognized to exert decisive effects on animal welfare.However,the factors influencing mammary health are still unclear.Differential s...Background:Mammary health is important for transition dairy cows and has been well recognized to exert decisive effects on animal welfare.However,the factors influencing mammary health are still unclear.Differential somatic cell count(DSCC)could reflect the mastitis risk since it is the percentage of neutrophils plus lymphocytes in total somatic cells and could be reflective of mammary health of dairy cows.This work aimed to investigate the assessment and prognosis of the health of transition cows based on blood neutrophil extracellular traps(NETs).Results:Eighty-four transition Holstein dairy cows were selected.The serum was sampled in all the animals at week 1 pre-and postpartum,and milk was sampled at week 1 postpartum.Based on the DSCC in milk at week 1,cows with lower(7.4%±4.07%,n=15)and higher(83.3%±1.21%,n=15)DSCCs were selected.High DSCC cows had higher levels of red blood cell counts(P<0.05),hemoglobin(P=0.07),and hematocrit(P=0.05),higher concentrations of serum oxidative variables[reactive oxygen species(P<0.05),malondialdehyde(P<0.05),protein carbonyl(P<0.05),and 8-hydroxy-2-deoxyguanosine(P=0.07)],higher levels of serum and milk NETs(P<0.05)and blood-milk barrier indicators,including serumβ-casein(P=0.05)and milk immunoglobulin G2(P=0.09),than those of low DSCC cows.In addition,lower concentrations of serum nutrient metabolites(cholesterol and albumin)(P<0.05)and a lower level of serum deoxyribonuclease I(P=0.09)were observed in high DSCC cows than in low DSCC cows.Among the assessments performed using levels of the three prepartum serum parameters(NETs,deoxyribonuclease I andβ-casein),the area under the curve(0.973)of NETs was the highest.In addition,the sensitivity(1.00)and specificity(0.93)were observed for the discrimination of these cows using NETs levels with a critical value of 32.2 ng/mL(P<0.05).Conclusions:The formation of NETs in blood in transition dairy cows may damage the integrity of the blood-milk barrier and thereby increase the risk for mastitis in postpartum cows.展开更多
Objective:Liver cancer is a deadly malignancy associated with high mortality and morbidity.Less than 20%of patients with advanced liver cancer respond to a single anti-PD-1 treatment.The high heterogeneity of neutroph...Objective:Liver cancer is a deadly malignancy associated with high mortality and morbidity.Less than 20%of patients with advanced liver cancer respond to a single anti-PD-1 treatment.The high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade(ICB).However,the underlying mechanism remains largely unknown.Methods:We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12Dinto the genome in liver cells from conditional Trp53 null/null mice(pTMK/Trp53^(-/-)).Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor microenvironment.An ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils(TANs)on CD8^(+)T cells.The roles of neutrophils,T cells,and NK cells were validated through antibody-mediated depletion.The efficacy of the combination of neutrophil depletion and ICB was evaluated.Results:Orthotropic pTMK/Trp53^(-/-)mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 blockade.Depletion of neutrophils increased the infiltration of CD8^(+)T cells and decreased the number of exhausted T cells in the tumor microenvironment.Furthermore,depletion of either CD8^(+)T or NK cells abrogated the antitumor efficacy of anti-Ly6G treatment.Moreover,the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8^(+)T cells and thereafter resulted in a significantly greater decrease in tumor burden.Conclusions:Our data suggest that TANs may contribute to the resistance of liver cancer to ICB,and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.展开更多
Familial adenomatous polyposis(FAP)is an autosomal dominant disease with a high probability of becoming cancerous.Many RNAs potentially associated with FAP have not been identified.In this study,a circRNA(circular RNA...Familial adenomatous polyposis(FAP)is an autosomal dominant disease with a high probability of becoming cancerous.Many RNAs potentially associated with FAP have not been identified.In this study,a circRNA(circular RNA)expression profile of FAP was established using a circRNA microarray,and differentially expressed circRNAs were verified by RT-qPCR.The effects of hsa_circ_0036740 on the malignant behavior of tumor cells(proliferation,apoptosis,and epithelial mesenchymal transition)and the levels of C3A complement protein expression were evaluated.Moreover,neutrophils were isolated and co-cultured with colorectal cancer cells(CRCs),followed by measurements of MPO-DNA,citrullinated histone H3,interleukin(IL)-1β,IL-6,and IL-8 levels.Nuclear translocation of arginine deiminase 4(PAD4)was observed using immunofluorescence assays.Based on the high-throughput assay,238 downregulated circRNAs,and 38 upregulated circRNAs were identified.A Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that immune regulation might be involved in FAP.A total of 10 DECs(differentially expressed circular RNAs)were identified by RT-qPCR,and among them,hsa_circ_0036740 showed the highest fold-change in upregulation.Results of gain-of-and loss-of-function studies revealed that hsa_circ_0036740 enhanced the malignant behavior of tumor cells,such as metastasis,proliferation,and apoptosis,with an increasing level of C3A complement.Moreover,hsa_circ_0036740 also significantly increased neutrophil extracellular trap formation and inflammation in neutrophils,as shown by an increased expression of PAD4.In conclusion,this study revealed the expression profiles of circRNAs in FAP and confirmed the possible involvement of hsa_circ_0036740 in the immune regulation mediated by neutrophils.Finally,hsa_circ_0036740 was suggested as a new therapeutic target for CRC.展开更多
Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-...Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy.In this study,sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood,blocked neutrophil accumulation in tumors,and attenuated the inhibitory effect of infiltrating neutrophils on T cells.Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer.Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils.Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8^(+) T lymphocytes in the tumor.The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.展开更多
Objective:To explore the possible mechanism of neutrophil exosomes regulating macrophage apoptosis.Methods:neutrophils were induced by lipopolysaccharide,inflammatory factors were detected by ELISA,the morphology of e...Objective:To explore the possible mechanism of neutrophil exosomes regulating macrophage apoptosis.Methods:neutrophils were induced by lipopolysaccharide,inflammatory factors were detected by ELISA,the morphology of exosomes was identified by electron microscope,and the expression of mir-15a-5p in exosomes was detected by RT-PCR;Raw267.4 macrophages was treated with neutrophil exosomes and mir-15a-5p mimic respectively,CCK8 to detect cell viability,flow cytometry to detect apoptosis;The binding sites of mir-15a-5p and BCL2L2 were predicted and verified by double luciferase experiment;RT-PCR and Western blot verified that mir-15a-5p regulate the expression of BCL2L2.Results:lipopolysaccharide induced neutrophil inflammatory factors IL-2,IL-6,IL-10 and TNF-α.The morphological characteristics of exosomes were observed by electron microscope.Mir-15a-5p was significantly overexpressed in neutrophil exosomes induced by lipopolysaccharide;Lipopolysaccharide-induced neutrophil exosomes and mir-15a-5p simulants can promote raw267.4 macrophage apoptosis and inhibit its cell viability;Targetscan database predicted that mir-15a-5p and BCL2L2 had binding sites.Double-luciferase experiment verified that mir-15a-5p and BCL2L2 bound through binding sites;Mir-15a-5p mimic was transfected into raw267.4 macrophages which inhibit the expression of BCL2L2 mRNA and protein.Conclusion:inflammatory neutrophils may promote raw267.4 by secreting exosomes containing mir-15a-5p and inhibiting BCL2L2 by targeting macrophage apoptosis.This may provide a theoretical basis for further understanding the molecular mechanism of inflammatory regulation of neutrophils and macrophages.展开更多
Background: In developed countries, colon cancer is the second most prevalent cancer, only exceeded by prostate cancer in men and breast cancer in women. After Hepatocellular carcinoma, breast cancer, bladder cancer, ...Background: In developed countries, colon cancer is the second most prevalent cancer, only exceeded by prostate cancer in men and breast cancer in women. After Hepatocellular carcinoma, breast cancer, bladder cancer, lung cancer, Non-Hodgkin Lymphoma and brain tumors, colon cancer is the 7<sup>th</sup> most common cancer in Egypt, in both sexes, representing 3.47% and 3%, in both male and female cancers, respectively. Aim of the Work: The aim of this study was to evaluate the prognostic and predictive significance of pretreatment Neutrophil/lymphocytes ratio (NLR), in terms of disease-free survival (DFS) and recurrence, in high-risk stage II and stage III Colorectal cancer patients who underwent curative resection. Patients and Methods: We retrospectively evaluated 103 patients, who were submitted to upfront surgery as first therapeutic option in curative intent, between January 2017 and December 2018. Pretreatment Neutrophil/lymphocytes ratio (NLR), as well as demographics, clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with disease free survival (DFS) and recurrence. Results: The cutoff point of Neutrophils/lymphocytes ratio (NLR) was calculated with Kaplan-Meier curves and log-rank test to 3. This study revealed that neutrophils/lymphocytes ratio (NLR) was significantly associated with disease free survival (p as no difference in efficacy between both chemotherapy regimens FOLFOX and XELOX in both high-risk stage II and stage III colon cancer regarding disease free survival & the toxicity profile associated with each regimen and its grades between patients. Conclusion: Our study suggests that preoperative Neutrophils/lymphocytes ratio (NLR) more than 3 may be an independent prognostic marker for TTR (time to recurrence) in high-risk stage II and stage III colon cancer patients.展开更多
The mathematical model of stem cells is discussed with its motivation to describe the tissue relationship by technically introducing a two compartments model. The clear link between the proliferation phase of stem cel...The mathematical model of stem cells is discussed with its motivation to describe the tissue relationship by technically introducing a two compartments model. The clear link between the proliferation phase of stem cells and the circulating neutrophil phase is set forth after delay feedback control of the state variable of stem cells. Hopf bifurcation is discussed with varying free parameters and time delays. Based on the center manifold theory, the normal form near the critical point is computed and the stability of bifurcating periodical solution is rigorously discussed. With the aids of the artificial tool on-hand which implies how much tedious work doing by DDE-Biftool software, the bifurcating periodic solution after Hopf point is continued by varying time delay.展开更多
基金supported by the National Natural Science Foundation of China,No.82271399(to XC)the Project of Tianjin Applied Basic and Multiple Support Research,No.21JCZDJC00910(to XC)+4 种基金the Scientific Research Program of Tianjin Education Commission(Natural Science)of China,No.2019ZD034(to QD)the Science&Technology Program of Tianjin for Cultivation of Innovative Talents,No.22JRRCRC00020(to QD)the Tianjin Medical University"Clinical Talent Training 123 Climbing Plan"(to XC)the Tianjin Health Care Elite Prominent Young Doctor Development Program(to XC)the Young and Middle-aged Backbone Innovative Talent Program(to XC)。
文摘Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms.Histones,von Willebrand factor,fibrin,and many other factors participate in the interplay between inflammation and thrombosis.Neuroimmunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases,providing cutting-edge insights into post-neurotrauma thrombotic events.The blood-brain barrier defends the brain and spinal cord against external assaults,and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases.Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis,but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis,and identified modulators of neuro-immunothrombosis.However,these neurological diseases occur in blood vessels,and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury.This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.
基金supported by grants from the National Key R&D Program of China(Grant No.2018YFA0900900)the National Natural Science Foundation of China(Grant Nos.82273334,82203172,81871869,and 81400055)+3 种基金the Jiangsu Province Social Development Key Projects(Grant Nos.BE2020641 and BE2020640)the Xuzhou Medical University Excellent Talent Research Start-up Fund(Grant No.RC20552157)the Jiangsu Province Capability Improvement Project through Science,Technology and Education(Grant No.CXZX202234)funded by the China Postdoctoral Science Foundation(Grant No.2023M732970)。
文摘Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan–Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADPribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.
基金supported in part by the Japan Agency for Medical Research and Development (AMED) under grant number JP20ek0410073, JP23ek0410108, JP22ek0410100, AMEDCREST under grant number JP19gm1210008 and AMED-PRIME under grant number JP21gm6310029, the AMED Japan Initiative for World leading Vaccine Research and Development Centers (JP223fa627001)Japan Society for the Promotion of Science (JSPS): Scientific Research S (21H05046), Scientific Research B (21H03104, 22H03195, and 22H02844) and Challenging Research (20K21515 and 21K18254)+3 种基金the JST FOREST Program (JPMJFR2261, JPMJFR205Z)Y.A. was supported by a JSPS Research Fellowship for Young Scientists (23KJ1949)Japanese Society for Immunology (JSI)Kibou Scholarship for Doctoral Students in Immunology。
文摘The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune–bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNAsequencing analysis on mouse periodontal lesions and showed that neutrophil–osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.
基金supported by the National Natural Science Foundation of China,No.32371048(to YK)the Peking University People’s Hospital Research and Development Funds,No.RDX2021-01(to YK)the Natural Science Foundation of Beijing,No.7222198(to NH)。
文摘Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.
基金The research protocol was approved by the Clinical Trial Ethics Committee of the Affiliated Hospital of Southwest Medical University(approval number:KY2021063)registered in the Chinese Clinical Trial Registry(registration number:ChiCTR2100044198).
文摘BACKGROUND Circulating tumor cell(CTC)count and neutrophil-to-lymphocyte ratio(NLR)are both closely associated with the prognosis of hepatocellular carcinoma(HCC).AIM To investigate the prognostic value of combining these two indicators in HCC.METHODS Clinical data were collected from patients with advanced HCC who received im-mune therapy combined with targeted therapy at the Department of Oncology,the Affiliated Hospital of Southwest Medical University,Sichuan,China,from 2021 to 2023.The optimal cutoff values for CTC programmed death-ligand 1(PD-L1)(+)>1 or CTC PD-L1(+)≤1 and NLR>3.89 or NLR≤3.89 were evaluated using X-Tile software.Patients were categorized into three groups based on CTC PD-L1(+)counts and NLR:CTC-NLR(0),CTC-NLR(1),and CTC-NLR(2).The relationship between CTC-NLR and clinical variables as well as survival rates was assessed.RESULTS Patients with high CTC PD-L1(+)expression or NLR at baseline had shorter median progression-free survival(m-PFS)and median overall survival(mOS)than those with low levels of CTC PD-L1(+)or NLR(P<0.001).Mean-while,patients in the CTC-NLR(2)group showed a significant decrease in mPFS and mOS.Cox regression analysis revealed that alpha-fetoprotein(AFP),CTC PD-L1(+),and CTC-NLR were independent predictors of OS.The time-dependent receiver operating characteristic curve showed that the area under the curve of CTC-NLR at 12 months(0.821)and 18 months(0.821)was superior to that of AFP and CTC PD-L1(+).CONCLUSION HCC patients with high CTC PD-L1(+)or NLR expression tend to exhibit poor prognosis,and a high baseline CTC-NLR score may indicate low survival.CTC-NLR may serve as an effective prognostic indicator for patients with advanced HCC receiving immunotherapy combined with targeted therapy.
基金supported by grants from the National Traditional Chinese Medicine Inheritance and Innovation Project Fund(Development and Reform Office[2022]366)National Key Discipline of Traditional Chinese Medicine(Traditional Chinese Medicine[2023]No.85)+2 种基金the Ministry of Science and Technology National Key Research and Development Program Chinese Medicine Modernization Research Key Project(2018YFC1705204)National Nature Fund Program(82074373,82274490,82205090)Anhui Provincial Laboratory of Applied Basis and Development of Internal Medicine of Modern Traditional Chinese Medicine(2016080503B041).
文摘Rheumatoid arthritis(RA)is a prevalent autoimmune disease whose main features include chronic synovial inflammation,bone destruction,and joint degeneration.Neutrophils are often considered to be the first responders to inflammation and are a key presence in the inflammatory milieu of RA.Neutrophil extracellular traps(NETs),a meshwork of DNA-histone complexes and proteins released by activated neutrophils,are widely involved in the pathophysiology of autoimmune diseases,especially RA,in addition to playing a key role in the neutrophil innate immune response.NETs have been found to be an important source of citrullinated autoantigen antibodies and inflammatory factor release,which can activate RA synovial fibroblasts(FLS)and cause joint damage.This article reviews the role of NETs in the pathophysiology of RA,demonstrating the application of multiple molecules with various therapies,with a view to informing the discovery and development of novel biomarkers and therapeutic targets for RA.
文摘Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.
文摘Objective:To explore correlation of neutrophil-to-lymphocyte ratio(NLR)to severity of coronary artery disease(CAD)and in-hospital clinical outcomes in patients with acute coronary syndrome(ACS).Methods:In this prospective and observational study,we recruited 500 patients with ACS.For all the eligible patients,demographic details were collected,and laboratory parameters were evaluated.The CAD severity was evaluated in terms of the number of involved vessels.The NLR was calculated based on neutrophils and lymphocytes and the correlation of various risk factors and severity and outcome of CAD was performed.Results:77.2%of Patients was male,and 52%of the patients aged between 55-70 years.Based on the type of ACS,396 out of 500 patients had ST-elevation myocardial infarction.An ascending trend in the white blood cell levels and NLR value was noted as the severity of the ACS increased and the highest white blood cell levels and NLR was noted among classⅣpatients.The mean NLR value among the non-survivors were higher compared to the survivors(9.52±5.72 vs.4.76±2.36;P<0.01).Receiver operating curve showed that the cut-off NLR value was 5.76 with a sensitivity of 75.0%and a specificity of 77.3%.Conclusions:The NLR can be used as an independent prognostic marker in ACS.An elevated NLR value serves as a reliable predictor for short-term complications,notably in-hospital mortality.
基金Supported by Self-financing Project of Chengde Science and Technology Program in 2023(202303A079).
文摘[Objectives]This study was conducted to explore the relationship between neutrophil percentage-to-albumin ratio(NPAR)and coronary heart disease complicated with diabetes.[Methods]A total of 603 patients with coronary heart disease who underwent coronary angiography in Pingquan County Hospital from January,2023 to December,2023 and met the inclusion criteria were included as the research object.All the patients were divided into a coronary heart disease complicated with diabetes group(CAD+T2DM group)(n=298 cases)and a control group(CAD group)(n=305 cases),according to patients medical history,heart color ultrasound and biochemical test results.The clinical data,biochemical test results and coronary artery imaging data of patients were recorded,and the Gensini score was calculated.The neutrophil percentage(NEUT%)and albumin count were determined to calculate NPAR.[Results]The NPAR value of the coronary heart disease complicated with diabetes mellitus group was(1.6±0.42),which was significantly higher than that of the control group(1.47±0.49),and the difference was statistically significant(P<0.05).The area under the ROC curve was 0.619(95%CI:0.591-0.675,P<0.05),and the prediction of coronary heart disease complicated with diabetes using NPAR showed a Youden index of 0.31,a sensitivity of 60.4%,a specificity of 40.3%,and a best cut-off score of 1.4506.[Conclusions]The neutrophil percentage-to-albumin ratio(NPAR)is closely related to coronary heart disease complicated with diabetes mellitus,and NPAR has clinical application value in the diagnosis of coronary heart disease complicated with diabetes mellitus.
基金This work has been supported by the Liaoning Province Natural Science Foundation(Grant Nos.:2020-ZLLH-47,2020-MS-065,2021-YGJC-02,and 2017225054).Figures in the paper were drawn using Figdraw,and we sincerely thank the free drawing support provided by the Figdraw platform(www.fgdraw.com).We also would like to thank Editage(www.editage.cn)for English language editing.
文摘Neutrophil elastase(NE),a major protease in the primary granules of neutrophils,is involved in microbicidal activity.NE is an important factor promoting inflammation,has bactericidal effects,and shortens the inflammatory process.NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling.However,NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction.Additionally,it plays a complex role in various physiological processes and mediates several diseases.Sivelestat,a specific NE inhibitor,has strong potential for clinical application,particularly in the treatment of coronavirus disease 2019(COVID-19).This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.
基金supported by the National Natural Science Foundation of China,No. 81771327 (to BYL)Construction of Central Nervous System Injury Basic Science and Clinical Translational Research PlatformBudget of Beijing Municipal Health Commission 2020, No. PXM2020_026280_000002 (BYL)。
文摘After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury(sub-acute phase), genome-wide transcriptomic data showed that interleukin 17 A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17 A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17 A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17 A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17 A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17 A may be a promising therapeutic target for traumatic brain injury.
基金financially supported by the National Natural Science Foundation of China(31971318,21876205,22027810,and 32101091)China Postdoctoral Science Foundation(2021M690043)+2 种基金the Key-Area Research and Development Program of Guangdong Province(2020B0101020001)the Chinese Academy of Sciences(CAS)Key Research Program for Frontier Sciences(QYZDJSSW-SLH022)the CAS Interdisciplinary Innovation Team,and Big Data Program of PLA General Hospital(2017MBD-016)。
文摘Primary and metastatic lung cancers are malignant lung tumors each with of which has a different pathogenesis,although both threaten patient lives.Tumor development and progression involve communication between tumor cells and the host microenvironment.Neutrophils are the most abundant immune cells in the tumor microenvironment(TME);they participate in the generation of an inflammatory milieu and influence patient survival through their anti-and pro-tumor abilities.Neutrophils can be classified into various categories according to different criteria;frequent categories include N1 antitumor neutrophils and N2 immunosuppressive neutrophils.The antitumor effects of neutrophils are reported to be mediated through a combination of reactive oxygen species,tumor necrosis factor-related apoptosis-inducing ligand,and receptor for advanced glycation end-products–cathepsin G association,as well as the regulation of the activities of other immune cells.There have also been reports that neutrophils can function as tumor promoters that contribute to lung cancer progression and metastasis by influencing processes including carcinogenesis,angiogenesis,cancer cell proliferation,and invasion ability,as well as having similar roles in the lung metastasis of other cancers.The rapid development of nanotechnology has provided new strategies for cancer treatment targeting neutrophils.
基金This work was supported by grants from Guangxi Medical High-level Key Talents/139/(No.G201901010)Natural Science Foundation of Guangxi Province(No.GXNSFDA198008).
文摘Objective The hypersensitivity of the kidney makes it susceptible to hypoxia injury.The involvement of neutrophil extracellular traps(NETs)in renal injury resulting from hypobaric hypoxia(HH)has not been reported.In this study,we aimed to investigate the expression of NETs in renal injury induced by HH and the possible underlying mechanism.Methods A total of 24 SD male rats were divided into three groups(n=8 each):normal control group,hypoxia group and hypoxia+pyrrolidine dithiocarbamate(PDTC)group.Rats in hypoxia group and hypoxia+PDTC group were placed in animal chambers with HH which was caused by simulating the altitude at 7000 meters(oxygen partial pressure about 6.9 kPa)for 7 days.PDTC was administered at a dose of 100 mg/kg intraperitoneally once daily for 7 days.Pathological changes of the rat renal tissues were observed under a light microscope;the levels of serum creatinine(SCr),blood urea nitrogen(BUN),cell-free DNA(cf-DNA)and reactive oxygen species(ROS)were measured;the expression levels of myeloperoxidase(MPO),citrullinated histone H3(cit-H3),B-cell lymphoma 2(Bcl-2),Bax,nuclear factor kappa B(NF-κB)p65 and phospho-NF-κB p65(p-NF-κB p65)in rat renal tissues were detected by qRT-qPCR and Western blotting;the localization of NF-κB p65 expression in rat renal tissues was observed by immunofluorescence staining and the expression changes of NETs in rat renal tissues were detected by multiplex fluorescence immunohistochemical staining.Results After hypoxia,the expression of NF-κB protein in renal tissues was significantly increased,the levels of SCr,BUN,cf-DNA and ROS in serum were significantly increased,the formation of NETs in renal tissues was significantly increased,and a large number of tubular dilatation and lymphocyte infiltration were observed in renal tissues.When PDTC was used to inhibit NF-κB activation,NETs formation in renal tissue was significantly decreased,the expression level of Bcl-2 in renal tissues was significantly increased,the expression level of Bax was significantly decreased,and renal injury was significantly alleviated.Conclusion HH induces the formation of NETs through the NF-κB signaling pathway,and it promotes apoptosis and aggravates renal injury by decreasing Bcl-2 and increasing Bax expression.
基金financially supported by grants from the China-USA Intergovernmental Collaborative Project in S&T Innovation under the National Key R&D Program (No.2018YFE0111700,Beijing)。
文摘Background:Mammary health is important for transition dairy cows and has been well recognized to exert decisive effects on animal welfare.However,the factors influencing mammary health are still unclear.Differential somatic cell count(DSCC)could reflect the mastitis risk since it is the percentage of neutrophils plus lymphocytes in total somatic cells and could be reflective of mammary health of dairy cows.This work aimed to investigate the assessment and prognosis of the health of transition cows based on blood neutrophil extracellular traps(NETs).Results:Eighty-four transition Holstein dairy cows were selected.The serum was sampled in all the animals at week 1 pre-and postpartum,and milk was sampled at week 1 postpartum.Based on the DSCC in milk at week 1,cows with lower(7.4%±4.07%,n=15)and higher(83.3%±1.21%,n=15)DSCCs were selected.High DSCC cows had higher levels of red blood cell counts(P<0.05),hemoglobin(P=0.07),and hematocrit(P=0.05),higher concentrations of serum oxidative variables[reactive oxygen species(P<0.05),malondialdehyde(P<0.05),protein carbonyl(P<0.05),and 8-hydroxy-2-deoxyguanosine(P=0.07)],higher levels of serum and milk NETs(P<0.05)and blood-milk barrier indicators,including serumβ-casein(P=0.05)and milk immunoglobulin G2(P=0.09),than those of low DSCC cows.In addition,lower concentrations of serum nutrient metabolites(cholesterol and albumin)(P<0.05)and a lower level of serum deoxyribonuclease I(P=0.09)were observed in high DSCC cows than in low DSCC cows.Among the assessments performed using levels of the three prepartum serum parameters(NETs,deoxyribonuclease I andβ-casein),the area under the curve(0.973)of NETs was the highest.In addition,the sensitivity(1.00)and specificity(0.93)were observed for the discrimination of these cows using NETs levels with a critical value of 32.2 ng/mL(P<0.05).Conclusions:The formation of NETs in blood in transition dairy cows may damage the integrity of the blood-milk barrier and thereby increase the risk for mastitis in postpartum cows.
基金jointly supported by the National Natural Science Foundation of China(Grant Nos.81972735,82030079,and 81972656)Beijing Natural Science Foundation(Grant No.7212108)+2 种基金Michigan Medicine and PKU-HSC JI(Grant No.BMU2020JI005)Baidu Foundation(Grant No.2020BD015)Ying Shi Foundation。
文摘Objective:Liver cancer is a deadly malignancy associated with high mortality and morbidity.Less than 20%of patients with advanced liver cancer respond to a single anti-PD-1 treatment.The high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade(ICB).However,the underlying mechanism remains largely unknown.Methods:We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12Dinto the genome in liver cells from conditional Trp53 null/null mice(pTMK/Trp53^(-/-)).Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor microenvironment.An ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils(TANs)on CD8^(+)T cells.The roles of neutrophils,T cells,and NK cells were validated through antibody-mediated depletion.The efficacy of the combination of neutrophil depletion and ICB was evaluated.Results:Orthotropic pTMK/Trp53^(-/-)mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 blockade.Depletion of neutrophils increased the infiltration of CD8^(+)T cells and decreased the number of exhausted T cells in the tumor microenvironment.Furthermore,depletion of either CD8^(+)T or NK cells abrogated the antitumor efficacy of anti-Ly6G treatment.Moreover,the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8^(+)T cells and thereafter resulted in a significantly greater decrease in tumor burden.Conclusions:Our data suggest that TANs may contribute to the resistance of liver cancer to ICB,and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.
基金supported by The Scientific Research Cultivation Project of Meizhou People’s Hospital(No.PY-C2019001).
文摘Familial adenomatous polyposis(FAP)is an autosomal dominant disease with a high probability of becoming cancerous.Many RNAs potentially associated with FAP have not been identified.In this study,a circRNA(circular RNA)expression profile of FAP was established using a circRNA microarray,and differentially expressed circRNAs were verified by RT-qPCR.The effects of hsa_circ_0036740 on the malignant behavior of tumor cells(proliferation,apoptosis,and epithelial mesenchymal transition)and the levels of C3A complement protein expression were evaluated.Moreover,neutrophils were isolated and co-cultured with colorectal cancer cells(CRCs),followed by measurements of MPO-DNA,citrullinated histone H3,interleukin(IL)-1β,IL-6,and IL-8 levels.Nuclear translocation of arginine deiminase 4(PAD4)was observed using immunofluorescence assays.Based on the high-throughput assay,238 downregulated circRNAs,and 38 upregulated circRNAs were identified.A Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that immune regulation might be involved in FAP.A total of 10 DECs(differentially expressed circular RNAs)were identified by RT-qPCR,and among them,hsa_circ_0036740 showed the highest fold-change in upregulation.Results of gain-of-and loss-of-function studies revealed that hsa_circ_0036740 enhanced the malignant behavior of tumor cells,such as metastasis,proliferation,and apoptosis,with an increasing level of C3A complement.Moreover,hsa_circ_0036740 also significantly increased neutrophil extracellular trap formation and inflammation in neutrophils,as shown by an increased expression of PAD4.In conclusion,this study revealed the expression profiles of circRNAs in FAP and confirmed the possible involvement of hsa_circ_0036740 in the immune regulation mediated by neutrophils.Finally,hsa_circ_0036740 was suggested as a new therapeutic target for CRC.
基金This work was supported by the National Natural Science Foundation of China[grant number:81973271].
文摘Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy.In this study,sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood,blocked neutrophil accumulation in tumors,and attenuated the inhibitory effect of infiltrating neutrophils on T cells.Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer.Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils.Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8^(+) T lymphocytes in the tumor.The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.
基金National Natural Science Foundation of China (No.82060357)Hainan Natural Science Foundation (No.2019RC370,820RC757)Research Project of Hainan Provincial Health Commission (No.20A200021)。
文摘Objective:To explore the possible mechanism of neutrophil exosomes regulating macrophage apoptosis.Methods:neutrophils were induced by lipopolysaccharide,inflammatory factors were detected by ELISA,the morphology of exosomes was identified by electron microscope,and the expression of mir-15a-5p in exosomes was detected by RT-PCR;Raw267.4 macrophages was treated with neutrophil exosomes and mir-15a-5p mimic respectively,CCK8 to detect cell viability,flow cytometry to detect apoptosis;The binding sites of mir-15a-5p and BCL2L2 were predicted and verified by double luciferase experiment;RT-PCR and Western blot verified that mir-15a-5p regulate the expression of BCL2L2.Results:lipopolysaccharide induced neutrophil inflammatory factors IL-2,IL-6,IL-10 and TNF-α.The morphological characteristics of exosomes were observed by electron microscope.Mir-15a-5p was significantly overexpressed in neutrophil exosomes induced by lipopolysaccharide;Lipopolysaccharide-induced neutrophil exosomes and mir-15a-5p simulants can promote raw267.4 macrophage apoptosis and inhibit its cell viability;Targetscan database predicted that mir-15a-5p and BCL2L2 had binding sites.Double-luciferase experiment verified that mir-15a-5p and BCL2L2 bound through binding sites;Mir-15a-5p mimic was transfected into raw267.4 macrophages which inhibit the expression of BCL2L2 mRNA and protein.Conclusion:inflammatory neutrophils may promote raw267.4 by secreting exosomes containing mir-15a-5p and inhibiting BCL2L2 by targeting macrophage apoptosis.This may provide a theoretical basis for further understanding the molecular mechanism of inflammatory regulation of neutrophils and macrophages.
文摘Background: In developed countries, colon cancer is the second most prevalent cancer, only exceeded by prostate cancer in men and breast cancer in women. After Hepatocellular carcinoma, breast cancer, bladder cancer, lung cancer, Non-Hodgkin Lymphoma and brain tumors, colon cancer is the 7<sup>th</sup> most common cancer in Egypt, in both sexes, representing 3.47% and 3%, in both male and female cancers, respectively. Aim of the Work: The aim of this study was to evaluate the prognostic and predictive significance of pretreatment Neutrophil/lymphocytes ratio (NLR), in terms of disease-free survival (DFS) and recurrence, in high-risk stage II and stage III Colorectal cancer patients who underwent curative resection. Patients and Methods: We retrospectively evaluated 103 patients, who were submitted to upfront surgery as first therapeutic option in curative intent, between January 2017 and December 2018. Pretreatment Neutrophil/lymphocytes ratio (NLR), as well as demographics, clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with disease free survival (DFS) and recurrence. Results: The cutoff point of Neutrophils/lymphocytes ratio (NLR) was calculated with Kaplan-Meier curves and log-rank test to 3. This study revealed that neutrophils/lymphocytes ratio (NLR) was significantly associated with disease free survival (p as no difference in efficacy between both chemotherapy regimens FOLFOX and XELOX in both high-risk stage II and stage III colon cancer regarding disease free survival & the toxicity profile associated with each regimen and its grades between patients. Conclusion: Our study suggests that preoperative Neutrophils/lymphocytes ratio (NLR) more than 3 may be an independent prognostic marker for TTR (time to recurrence) in high-risk stage II and stage III colon cancer patients.
文摘The mathematical model of stem cells is discussed with its motivation to describe the tissue relationship by technically introducing a two compartments model. The clear link between the proliferation phase of stem cells and the circulating neutrophil phase is set forth after delay feedback control of the state variable of stem cells. Hopf bifurcation is discussed with varying free parameters and time delays. Based on the center manifold theory, the normal form near the critical point is computed and the stability of bifurcating periodical solution is rigorously discussed. With the aids of the artificial tool on-hand which implies how much tedious work doing by DDE-Biftool software, the bifurcating periodic solution after Hopf point is continued by varying time delay.
