Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson's disease.Triggering receptor expressed on myeloid cell-1(TREM-1)can amplify the inherent immune response,and crucially,regula...Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson's disease.Triggering receptor expressed on myeloid cell-1(TREM-1)can amplify the inherent immune response,and crucially,regulate inflammation.In this study,we found marked elevation of serum soluble TREM-1 in patients with Parkinson's disease that positively correlated with Parkinson's disease severity and dyskinesia.In a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease,we found that microglial TREM-1 expression also increased in the substantia nigra.Further,TREM-1 knockout alleviated dyskinesia in a mouse model of Parkinson's disease and reduced dopaminergic neuronal injury.Meanwhile,TREM-1 knockout attenuated the neuroinflammatory response,dopaminergic neuronal injury,and neutrophil migration.Next,we established an in vitro 1-methyl-4-phenyl-pyridine-induced BV2 microglia model of Parkinson's disease and treated the cells with the TREM-1 inhibitory peptide LP17.We found that LP17 treatment reduced apoptosis of dopaminergic neurons and neutrophil migration.Moreover,inhibition of neutrophil TREM-1 activation diminished dopaminergic neuronal apoptosis induced by lipopolysaccharide.TREM-1 can activate the downstream CARD9/NF-κB proinflammatory pathway via interaction with SYK.These findings suggest that TREM-1 may play a key role in mediating the damage to dopaminergic neurons in Parkinson's disease by regulating the interaction between microglia and peripheral neutrophils.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
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
Neutrophils,which originate from the bone marrow and are characterized by a segmented nucleus and a brief lifespan,have a crucial role in the body’s defense against infections and acute inflammation.Recent research h...Neutrophils,which originate from the bone marrow and are characterized by a segmented nucleus and a brief lifespan,have a crucial role in the body’s defense against infections and acute inflammation.Recent research has uncovered the complex roles of neutrophils as regulators in tumorigenesis,during which neutrophils exhibit a dualistic nature that promotes or inhibits tumor progression.This adaptability is pivotal within the tumor microenvironment(TME).In this review,we provide a comprehensive characterization of neutrophil plasticity and heterogeneity,aiming to illuminate current research findings and discuss potential therapeutic avenues.By delineating the intricate interplay of neutrophils in the TME,this review further underscores the urgent need to understand the dual functions of neutrophils with particular emphasis on the anti-tumor effects to facilitate the development of effective therapeutic strategies against cancer.展开更多
Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulatio...Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI,which provides insight into the heterogeneity,reprogramming activity,and versatility of neutrophils in TBI.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: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
Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses.With their abundant numbers,diverse function and short life span,these cells...Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses.With their abundant numbers,diverse function and short life span,these cells are at the forefront of immune responses,and have gained attention in recent years because of their presence in tumor sites.Neutrophil involvement pertains to tumor cells'ability to construct a suitable tumor microenvironment(TME)that accelerates their own growth and malignancy,by facilitating their interaction with surrounding cells through the circulatory and lymphatic systems,thereby influencing tumor development and progression.Studies have indicated both pro-and anti-tumor properties of infiltrating neutrophils.The TME can exploit neutrophil function,recruitment,and even production,thus resulting in pro-tumor properties of neutrophils,including promotion of genetic instability,tumor cell proliferation,angiogenesis and suppression of anti-tumor or inflammatory response.In contrast,neutrophils can mediate anti-tumor resistance by direct cytotoxicity to the tumor cells or by facilitating anti-tumor functions via crosstalk with T cells.Here,we summarize current knowledge regarding the effects of neutrophil heterogeneity under homeostatic and tumor conditions,including neutrophil phenotype and function,in cancer biology.展开更多
This review is intended to shed new light on the role of neutrophils in colorectal cancer and in the meanwhile emphasiz</span><span style="font-family:Verdana;">e</span><span style="...This review is intended to shed new light on the role of neutrophils in colorectal cancer and in the meanwhile emphasiz</span><span style="font-family:Verdana;">e</span><span style="font-family:""><span style="font-family:Verdana;"> the differences between rectal and colon cancer, strengthen and highlight the possibility of a clinical prognostic and predictive scoring (Sarandria Score). A novel scoring system described in this review can be used as inclusion criteria and as a predictive and prognostic scoring for stage III rectal cancer patients. </span><b><span style="font-family:Verdana;">Background:</span></b><span style="font-family:Verdana;"> Colorectal Cancer (CRC) is a major public health problem, representing the third most commonly diagnosed cancer in males and the second in females. Various studies have reported relevant differences related to CRC primary location site (right-sided colon, left-sided colon, rectum) including response to adjuvant chemotherapy and prognosis. In stage III CRC patients, previous findings showed that higher density of tumor-associated neutrophils (TANs) was associated with better response to 5-FU-based chemotherapy. </span><b><span style="font-family:Verdana;">Main topics:</span></b><span style="font-family:Verdana;"> In this review</span></span><span style="font-family:Verdana;">,</span><span style="font-family:Verdana;"> the current knowledge status on the role of neutrophils in colorectal cancer is assessed, including novel finding discovered by Dr</span><span style="font-family:Verdana;">.</span><span style="font-family:Verdana;"> Nicola Sarandria on the role of neutrophils in rectal cancer. It includes different factors which point to an anti-tumoral role of neutrophils in rectal cancer when in presence of chemotherapeutic agents (such as 5-fluorouracil). The clinical significance of TANs was assessed and whether it can be different depend</span><span style="font-family:Verdana;">ed</span><span style="font-family:""><span style="font-family:Verdana;"> on the location of the primary CRC (right-sided colon, left-sided colon, rectum). </span><b><span style="font-family:Verdana;">Conclusions:</span></b><span style="font-family:Verdana;"> This review officially highlights the possibility of a new clinical prognostic and predictive scoring (Sarandria Score) involving intratumoral neutrophilic infiltration in rectal cancer and the possibility of a new inclusion criteri</span></span><span style="font-family:Verdana;">on</span><span style="font-family:Verdana;"> based on this infiltrate for Stage III rectal cancer patients treated with 5-FU therapy. This review includes knowledge from data published on my medical degree thesis showing that higher levels of TANs densities were associated with better disease-free survival (DFS) in 5-FU treated patients affected by rectal cancer (while it was inversely related in patients without 5-FU therapy). This </span><span style="font-family:Verdana;">i</span><span style="font-family:Verdana;">s also further evidence in support of a possible conceptual division of what is now known as colorectal cancer into two separate entities: colon and rectal cancer.展开更多
Neutrophils that are mostly related to our body immunity and inflammatory responses are now considered to be an important player in contrast to tumor progression.Along with many controversies,there is much clear evide...Neutrophils that are mostly related to our body immunity and inflammatory responses are now considered to be an important player in contrast to tumor progression.Along with many controversies,there is much clear evidence that shows neutrophils promote the metastasis process via different modes of actions in a different time frame concerning the advancement of cancer.Not only impacting cell proliferation but also they are found to be helping tumor cells in many events like angiogenesis,immune escape,invasion,and finally it leads to cancer metastasis.Tumor microenvironment,key players of cancer growth and progression are also affected by mostly neutrophils and it’s secretory.Tumor associated neutrophils,having certainly different characteristics and expressions,are found high in number around the tumor site and often in pre-metastatic niches.Increased number of premature neutrophils and more neutrophil-extracellular-traps formation is associated with a high degree of metastasis in cancer is observed.As neutrophils has potential role in cancer,more research are warranted in this field to fully understood the overall role of this immune cells and it will helps to open a new way to target neutrophils in therapeutic implications for better cancer treatment.Here we gather currents profile of neutrophils and its role in cancer metastasis and discuss therapeutics strategy.展开更多
The effects of berbamine, an alkaloid of dibenzylisoquinoline, on PAF produc tion in human neutrophils and on platelet aggregation induced by PAF were studied and compared with those of the calcium antagonist verapam...The effects of berbamine, an alkaloid of dibenzylisoquinoline, on PAF produc tion in human neutrophils and on platelet aggregation induced by PAF were studied and compared with those of the calcium antagonist verapamil. Preincubation with berbamine (50 mmol / L, 100 mmol / L) or verapamil (10 mmol / L, 100 mmol / L) was shown to significantly inhibit A 23187 stimulated PAF synthesis. Berbamine and verapamil were found to inhibit platelet aggregation induced by PAF 70 pmol / L in a dose dependent manner. These results suggest that the inhibitory effects of berbamine and verapamil on A 23187 stimulated PAF synthesis in human neutrophils and PAF induced platelet aggregation are possibly brought about by inhibiting cellular calcium influx.展开更多
Luteolin is an active ingredient found early from Fofium perillae and Flos Ionicerae, and has a specific inhibition on phosphodiesterase 4 （PDE4） activity in vitro. Researches show luteolin has pharmacological effec...Luteolin is an active ingredient found early from Fofium perillae and Flos Ionicerae, and has a specific inhibition on phosphodiesterase 4 （PDE4） activity in vitro. Researches show luteolin has pharmacological effects of anti-inflammation, anti-anaphylaxis, antitumor, antioxidant, protection of nervous system and so on, and has mainly been used for the treatment of respiratory inflammatory diseases, cancer and cardiovascular disease in clinic. PDE4, specific to hydrolyze cyclic AMP （cAMP）, is considered to be a new anti-inflammatory target due to the decisive role on cAMP signal in inflammatory cells such as neutrophils. In order to explore the anti-inflammatory mechanism, we further studied the effects of luteolin on the activity and expression of PDE4, the expression of lymphocyte function-associated antigen-1 （LFA-1） and macrophage-1 （MAC-l） in neutrophils, and the adhesion of neutrophils and endothelial cells. The results showed that luteolin had a dose-dependent inhibition on both bare PDE4 activity and PDE4 in cultured neutrophils, and had an obviously promotive effect on gene expressions of PDE4A, 4B and 4D in later period. Luteolin had a significant inhibitory effect on neutrophils adhesion and LFA-1 expression in early stage, and had no obvious effect on MAC-1 expression. Therefore, luteolin can inhibit LFA-1 expression of neutrophils, then inhibit the adhesion of neutrophils and endothelial cells, and the mechanism is at least related with the inhibition of PDE4 activity.展开更多
Our previous studies showed that the anti-inflammatory effects of Paeonia lactiflora roots extract may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inh...Our previous studies showed that the anti-inflammatory effects of Paeonia lactiflora roots extract may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inhibition on c AMP-phosphodiesterase（PDE）. To explore the anti-inflammatory effect and mechanism, the influence of gallic acid on neutrophils PDE4 activity and expression, TNF-α and IL-6 content and rat arthritis model were further studied. PDE4 activity and gene express were calculated respectively by substrate c AMP change examined with HPLC and real-time RT-PCR. The concentration of IL-6 and TNF-α in supernatant were assayed by ELISA method. Model of rat arthritis was caused by complete Freund＇s adjuvant. Results showed that gallic acid had a dose-dependent restraint on PDE4 activity of neutrophils in vitro, promoted significantly PDE4 A expression（P〈0.01）, and had no influence on the expressions of PDE4 B and 4D. However, PDE4 C expression was not detected. Gallic acid could promote IL-6 release（P〈0.05）, and inhibit TNF-α release of neutrophils（P〈0.05）. The experiment in vivo showed that gallic acid had obvious restraint on local inflammation of animal model（P〈0.05）. Therefore, the anti-inflammatory effect of gallic acid may be mediated in part through an inhibition on PDE4 activity and further an increase of IL-6 and a decrease of TNF-α of neutrophils, and this effect seemed to have no relationship with PDE4 expression.展开更多
Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthrit...Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis(RA)due to recently discovered neutrophil extracellular trap(NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.展开更多
Selectins are carbohydrate-binding cell adhesion molecules that play a major role in the initiation of inflammatory responses. Accumulaed evidence has suggested that heparin＇s anti-inflammatory effects are mainly med...Selectins are carbohydrate-binding cell adhesion molecules that play a major role in the initiation of inflammatory responses. Accumulaed evidence has suggested that heparin＇s anti-inflammatory effects are mainly mediated by blocking L-or P-selectin-initiated cell adhesion. Recently, we have reported that periodate-oxidized, borohydridereduced heparin （RO-heparln） can inhibit P-selectin-mediated acute inflammation. Here we further examined the effect of RO-heparin on the adhesion of L-selectin-mediated leukocytes to vascular endothelium under flow conditions in vivo and in vitro. The results show that RO-heparin with a low anticoagulant activity can effectively reduce leucocyte roiling on thioglycoUate-induced rat mesenterlc venules and L-selectin-metadiated neutrophil roiling on TNF-α-induced human umbilical vein endothelial cells（HUVECs） under flow conditions. Our findings suggest that the effect of RO-heparin on inflammatory responses is mainly a result of its inhibiting the interaction between P- or L-selectin and its ligands. The findings also suggest that RO-heparin may be useful in preventing inflammation diseases.展开更多
BACKGROUND:Patients with sepsis often exhibit an acute inflammatory response,followed by an immunosuppressive phase with a poor immune response.However,the underlying mechanisms have not been fully elucidated.METHODS:...BACKGROUND:Patients with sepsis often exhibit an acute inflammatory response,followed by an immunosuppressive phase with a poor immune response.However,the underlying mechanisms have not been fully elucidated.METHODS:We sought to comprehensively characterize the transcriptional changes in neutrophils of patients with sepsis by transcriptome sequencing.Additionally,we conducted a series of experiments,including real-time quantitative polymerase chain reaction(RT-qPCR)and flow cytometry to investigate the role of arginase-1 signaling in sepsis.RESULTS:Through the analysis of gene expression profiles,we identified that the negative regulation of T cell activation signaling was enriched,and the expression of arginase-1 was high in neutrophils from patients with sepsis.Furthermore,we conducted flow cytometry and found that the function of CD8^(+)T cells in septic patients was impaired.Moreover,neutrophils from septic patients inhibited the percentage of polyfunctional effector CD8^(+)T cells through arginase-1.Additionally,the proportions of granzyme B^(+)IFN^(-)γ^(+)CD8^(+)T and TNF^(-)α^(+)IFN^(-)γ^(+)CD8^(+)T cells increased after inhibition of arginase-1 signaling.CONCLUSION:The impaired effector function of CD8^(+)T cells could be restored by blocking arginase-1 signaling in patients with sepsis.展开更多
AIM: To explore the effect of indoleamine 2,3-dioxygenase(IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus(A.fumigatus) keratitis.METHODS: C57BL/6 mice models of A.fumigatus keratiti...AIM: To explore the effect of indoleamine 2,3-dioxygenase(IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus(A.fumigatus) keratitis.METHODS: C57BL/6 mice models of A.fumigatus keratitis were established by inoculating hyphae of A.fumigatus evenly on the corneas.The clinical scores and inflammatory cytokines expression were measured respectively on the 1^(st), 3^(th), 5^(th) day after infection.The 1-MT(1 mg/m L) was administered by gavage to exert an inhibitory effect on IDO during infection.The mice were divided into control group, 1-MT group, A.fumigatus(A.F.) group, and 1-MT+A.F.groups.The corneas were monitored by slit lamp microscopy, and recorded disease scores in 3 d after infection.Myeloperoxidase(MPO) assay was done to evaluate the neutrophils infiltration.Immunofluorescence staining was used to detect the recruitment of neutrophils in murine corneas.The m RNA of inflammatory cytokines was measured with reverse transcription-polymerase chain reaction(RT-PCR).RESULTS: The corneal inflammation and the clinical score reached the peak on the 3;day after the corneal infection.The m RNA of inflammatory cytokines of the A.F.group reached the highest on the 3;day after the infection accordingly.Meanwhile, the results of slit light photography indicated that inhibitors of IDO made inflammation more serious contrasted with the A.F.group on the 3;day.Besides, imunofluorescence staining and MPO indicated that 1-MT enhanced the recruitment, infiltration and chemotaxis of neutrophils obviously in contrast to the A.F.group.RT-PCR indicated that 1-MT increased the expression of CXCL-1, ICAM-1, IL-1β, and IL-8 significantly.CONCLUSION: IDO participates in the pathogenesis of A.fumigatus keratitis and plays an important role in inducing immune protection by inhibiting neutrophils-related inflammatory reaction and suppressing recruitment and chemotaxis of the neutrophils.展开更多
Objective： It was known that neutrophils play an important role in ischemic-reperfusion injury. In this study we tested the effect and its mechanism of dipyfidamole on neutrophils. Methods：Hydrogen peroxide（H2O2） ...Objective： It was known that neutrophils play an important role in ischemic-reperfusion injury. In this study we tested the effect and its mechanism of dipyfidamole on neutrophils. Methods：Hydrogen peroxide（H2O2） production by neutrophils was determined using luminol amplified chemiluminescence and the percentage of activity was calculated by observing the uninhibited peak height. Results： Dipyfidamole per se produced a concentration-dependent inhibition of H2O2 by formyl-MetleuPhe（fMLP）-stimulated neutrophils. Dipyridamole at a low concentration（0.3 μ mol · L^-1） that per se affected neutrophils only slightly, enhanced markedly the effects of adenosine on neutrophils. On the other hand, dipyfidamole did not alter the inhibitory effect of NECA（5＇ -N-ethylcarboxamidoadenosine） on neutrophils. However, propentofylline, a known inhibitor of adenosine uptake, also gotten the same result. Conclusion：Dipyfidamole inhibited the production of H2O2 by fMLP-sfimulated neutrophils. Dipyfidamole at a low concentration enhanced the inhibitory effect of adenosine on neutrophils. The mechanism involved is probably due to the effect of dipyfidamole on adenosine uptake.展开更多
<span style="font-family:Verdana;">Neutrophils are the most numerous leukocyte in mammals and normally they are the first phagocyte observed in recently damaged or infected tissues. They play a key rol...<span style="font-family:Verdana;">Neutrophils are the most numerous leukocyte in mammals and normally they are the first phagocyte observed in recently damaged or infected tissues. They play a key role </span><span style="font-family:Verdana;">in</span><span style="font-family:;" "=""><span><span style="font-family:Verdana;"> the innate immune responses to </span><i></i></span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> and several other microorganisms, nonetheless an exacerbated neutrophils activity can generate a harmful response to the host, therefore its turnover rate is very important to maintain the homeostasis and averts the host tissue damage. Both apoptosis followed by phagocytosis by mononuclear phagocytes (eferocytosis) and reverse transmigration have been considered the main processes for the clearance of neutrophils from injured or infected tissues. However, the interaction with </span><i></i></span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> and other microbes, as well as molecules produced by arthropod vectors such as sandflies saliva can modify the behavior of neutrophils, causing immediate lysis to prolong their life. In fact, as a result of a long course of coevolution, several microorganisms have developed skills to avoid neutrophil effector mechanisms and take advantage of neutrophil clearance pathways to promote their spread in the host’s body. </span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;">, </span><i><i><span style="font-family:Verdana;">Chlamydia pneumoniae</span></i><span></span></i><span style="font-family:Verdana;"> and </span><i><i><span style="font-family:Verdana;">Yersinia pestis</span></i><span></span></i><span style="font-family:Verdana;"> for example use the efferocytic Trojan horse process for their dissemination and immune protection, in a different way vaccinia Ankara virus and </span><i><i><span style="font-family:Verdana;">Toxoplasma gondii</span></i><span></span></i><span style="font-family:Verdana;"> exploit the neutrophil reverse transmigration for the same reason. Here we present an overview of some characteristics of neutrophils and their different destinations after interaction with several microorganisms, with an emphasis on </span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> species. It was also suggested the probable role of neutrophils reverse transmigration as another possible route for the spreading of </span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> in the visceral leishmaniasis.</span>展开更多
Objective:Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA).In this study,we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-media...Objective:Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA).In this study,we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-mediated inflammation in RA.Methods:Freund's complete adjuvant-induced arthritis was used as the murine model of RA.Celastrol was intraperitoneally administrated daily after onset of the disease.The joint diameter and inflammatory score were evaluated daily during the treatment period.Myeloperoxidase (MPO) and neutrophil elastase (NE) activities were evaluated by immunohistochemical analyses.Quantitative PCR and enzyme-linked immunoabsorbent assay were used to quantify the expression of cytokines.The expression of apoptosis-related proteins Bcl-2,Bax and caspase-3 were evaluated by western blot.Results:Celastrol suppressed inflammation in joints of arthritic mice and diminished the expression of MPO and NE in the joint tissue.Celastrol significantly inhibited the expression of TNFα and IL-6 induced by LPS in neutrophils in a dose-dependent manner in vitro.Moreover,celastrol induced apoptosis of LPS-stimulated neutrophils by increasing the expression of Bax and cleaved caspase-3 while decreasing Bcl-2 expression.Conclusion:Our findings show that celastrol significantly alleviates murine arthritis by modulating the inflammatory activities of neutrophils.These results indicate that celastrol could serve as an alternative or adjunct modality for the treatment of RA.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271257(to YZ)and 82071228(to YZ)Qing Lan Project(to YZ)+1 种基金Open Competition Grant of Xuzhou Medical University(to YZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.KYCX21_2705(to TS)。
文摘Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson's disease.Triggering receptor expressed on myeloid cell-1(TREM-1)can amplify the inherent immune response,and crucially,regulate inflammation.In this study,we found marked elevation of serum soluble TREM-1 in patients with Parkinson's disease that positively correlated with Parkinson's disease severity and dyskinesia.In a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease,we found that microglial TREM-1 expression also increased in the substantia nigra.Further,TREM-1 knockout alleviated dyskinesia in a mouse model of Parkinson's disease and reduced dopaminergic neuronal injury.Meanwhile,TREM-1 knockout attenuated the neuroinflammatory response,dopaminergic neuronal injury,and neutrophil migration.Next,we established an in vitro 1-methyl-4-phenyl-pyridine-induced BV2 microglia model of Parkinson's disease and treated the cells with the TREM-1 inhibitory peptide LP17.We found that LP17 treatment reduced apoptosis of dopaminergic neurons and neutrophil migration.Moreover,inhibition of neutrophil TREM-1 activation diminished dopaminergic neuronal apoptosis induced by lipopolysaccharide.TREM-1 can activate the downstream CARD9/NF-κB proinflammatory pathway via interaction with SYK.These findings suggest that TREM-1 may play a key role in mediating the damage to dopaminergic neurons in Parkinson's disease by regulating the interaction between microglia and peripheral neutrophils.
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.
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.
基金supported by the National Natural Science Foundation of China(Grant Nos.82130077,81961128025,and 82121002)the Research Projects from the Science and Technology Commission of Shanghai Municipality(Grant Nos.21JC1401200,20JC1418900,and 21JC1410100)to QG,the China National Postdoctoral Program for Innovative Talents(Grant No.BX20240090)the China Postdoctoral Science Foundation(Grant No.2024M750551)to MZ.
文摘Neutrophils,which originate from the bone marrow and are characterized by a segmented nucleus and a brief lifespan,have a crucial role in the body’s defense against infections and acute inflammation.Recent research has uncovered the complex roles of neutrophils as regulators in tumorigenesis,during which neutrophils exhibit a dualistic nature that promotes or inhibits tumor progression.This adaptability is pivotal within the tumor microenvironment(TME).In this review,we provide a comprehensive characterization of neutrophil plasticity and heterogeneity,aiming to illuminate current research findings and discuss potential therapeutic avenues.By delineating the intricate interplay of neutrophils in the TME,this review further underscores the urgent need to understand the dual functions of neutrophils with particular emphasis on the anti-tumor effects to facilitate the development of effective therapeutic strategies against cancer.
基金This work was supported by the National Natural Science Foundation of China(82071779 and 81901626)the Science Fund for Creative Research Groups of Chongqing Municipal Education Commission of China,the grants from the Talent Foundation of Army Medical University(to Shuang-Shuang Dai)+1 种基金the Scientific Research Grant(ALJ22J003)the Chongqing Natural Science Foundation of China(CSTB2022NSCQ-MSX0177).
文摘Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI,which provides insight into the heterogeneity,reprogramming activity,and versatility of neutrophils in TBI.
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A.Y.H. was supported by NRSA Institutional Postdoctoral Training grant T32 (Grant No. 5T32HL066987-20)C.S. was supported by grants from the National Natural Science Foundation of China (Grant No. 82001661)+1 种基金F.X.M. and C.S. were supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund (Grant No. HH22KYZX0019)F.X.M. was supported by the National Natural Science Foundation of China (Grant No. 82171756)
文摘Neutrophils play an essential role in the defense against bacterial infections and orchestrate both the innate and adaptive immune responses.With their abundant numbers,diverse function and short life span,these cells are at the forefront of immune responses,and have gained attention in recent years because of their presence in tumor sites.Neutrophil involvement pertains to tumor cells'ability to construct a suitable tumor microenvironment(TME)that accelerates their own growth and malignancy,by facilitating their interaction with surrounding cells through the circulatory and lymphatic systems,thereby influencing tumor development and progression.Studies have indicated both pro-and anti-tumor properties of infiltrating neutrophils.The TME can exploit neutrophil function,recruitment,and even production,thus resulting in pro-tumor properties of neutrophils,including promotion of genetic instability,tumor cell proliferation,angiogenesis and suppression of anti-tumor or inflammatory response.In contrast,neutrophils can mediate anti-tumor resistance by direct cytotoxicity to the tumor cells or by facilitating anti-tumor functions via crosstalk with T cells.Here,we summarize current knowledge regarding the effects of neutrophil heterogeneity under homeostatic and tumor conditions,including neutrophil phenotype and function,in cancer biology.
文摘This review is intended to shed new light on the role of neutrophils in colorectal cancer and in the meanwhile emphasiz</span><span style="font-family:Verdana;">e</span><span style="font-family:""><span style="font-family:Verdana;"> the differences between rectal and colon cancer, strengthen and highlight the possibility of a clinical prognostic and predictive scoring (Sarandria Score). A novel scoring system described in this review can be used as inclusion criteria and as a predictive and prognostic scoring for stage III rectal cancer patients. </span><b><span style="font-family:Verdana;">Background:</span></b><span style="font-family:Verdana;"> Colorectal Cancer (CRC) is a major public health problem, representing the third most commonly diagnosed cancer in males and the second in females. Various studies have reported relevant differences related to CRC primary location site (right-sided colon, left-sided colon, rectum) including response to adjuvant chemotherapy and prognosis. In stage III CRC patients, previous findings showed that higher density of tumor-associated neutrophils (TANs) was associated with better response to 5-FU-based chemotherapy. </span><b><span style="font-family:Verdana;">Main topics:</span></b><span style="font-family:Verdana;"> In this review</span></span><span style="font-family:Verdana;">,</span><span style="font-family:Verdana;"> the current knowledge status on the role of neutrophils in colorectal cancer is assessed, including novel finding discovered by Dr</span><span style="font-family:Verdana;">.</span><span style="font-family:Verdana;"> Nicola Sarandria on the role of neutrophils in rectal cancer. It includes different factors which point to an anti-tumoral role of neutrophils in rectal cancer when in presence of chemotherapeutic agents (such as 5-fluorouracil). The clinical significance of TANs was assessed and whether it can be different depend</span><span style="font-family:Verdana;">ed</span><span style="font-family:""><span style="font-family:Verdana;"> on the location of the primary CRC (right-sided colon, left-sided colon, rectum). </span><b><span style="font-family:Verdana;">Conclusions:</span></b><span style="font-family:Verdana;"> This review officially highlights the possibility of a new clinical prognostic and predictive scoring (Sarandria Score) involving intratumoral neutrophilic infiltration in rectal cancer and the possibility of a new inclusion criteri</span></span><span style="font-family:Verdana;">on</span><span style="font-family:Verdana;"> based on this infiltrate for Stage III rectal cancer patients treated with 5-FU therapy. This review includes knowledge from data published on my medical degree thesis showing that higher levels of TANs densities were associated with better disease-free survival (DFS) in 5-FU treated patients affected by rectal cancer (while it was inversely related in patients without 5-FU therapy). This </span><span style="font-family:Verdana;">i</span><span style="font-family:Verdana;">s also further evidence in support of a possible conceptual division of what is now known as colorectal cancer into two separate entities: colon and rectal cancer.
文摘Neutrophils that are mostly related to our body immunity and inflammatory responses are now considered to be an important player in contrast to tumor progression.Along with many controversies,there is much clear evidence that shows neutrophils promote the metastasis process via different modes of actions in a different time frame concerning the advancement of cancer.Not only impacting cell proliferation but also they are found to be helping tumor cells in many events like angiogenesis,immune escape,invasion,and finally it leads to cancer metastasis.Tumor microenvironment,key players of cancer growth and progression are also affected by mostly neutrophils and it’s secretory.Tumor associated neutrophils,having certainly different characteristics and expressions,are found high in number around the tumor site and often in pre-metastatic niches.Increased number of premature neutrophils and more neutrophil-extracellular-traps formation is associated with a high degree of metastasis in cancer is observed.As neutrophils has potential role in cancer,more research are warranted in this field to fully understood the overall role of this immune cells and it will helps to open a new way to target neutrophils in therapeutic implications for better cancer treatment.Here we gather currents profile of neutrophils and its role in cancer metastasis and discuss therapeutics strategy.
文摘The effects of berbamine, an alkaloid of dibenzylisoquinoline, on PAF produc tion in human neutrophils and on platelet aggregation induced by PAF were studied and compared with those of the calcium antagonist verapamil. Preincubation with berbamine (50 mmol / L, 100 mmol / L) or verapamil (10 mmol / L, 100 mmol / L) was shown to significantly inhibit A 23187 stimulated PAF synthesis. Berbamine and verapamil were found to inhibit platelet aggregation induced by PAF 70 pmol / L in a dose dependent manner. These results suggest that the inhibitory effects of berbamine and verapamil on A 23187 stimulated PAF synthesis in human neutrophils and PAF induced platelet aggregation are possibly brought about by inhibiting cellular calcium influx.
基金financial support of the Beijing Natural Science Foundation, China (6112007)the National Natural Science Foundation of China (31101851)+1 种基金the Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality, China (PHR201107134)the Comprehensive Reforming Project to promote talents training of Beijing University of Agriculture, China (BNRC&GG201404)
文摘Luteolin is an active ingredient found early from Fofium perillae and Flos Ionicerae, and has a specific inhibition on phosphodiesterase 4 （PDE4） activity in vitro. Researches show luteolin has pharmacological effects of anti-inflammation, anti-anaphylaxis, antitumor, antioxidant, protection of nervous system and so on, and has mainly been used for the treatment of respiratory inflammatory diseases, cancer and cardiovascular disease in clinic. PDE4, specific to hydrolyze cyclic AMP （cAMP）, is considered to be a new anti-inflammatory target due to the decisive role on cAMP signal in inflammatory cells such as neutrophils. In order to explore the anti-inflammatory mechanism, we further studied the effects of luteolin on the activity and expression of PDE4, the expression of lymphocyte function-associated antigen-1 （LFA-1） and macrophage-1 （MAC-l） in neutrophils, and the adhesion of neutrophils and endothelial cells. The results showed that luteolin had a dose-dependent inhibition on both bare PDE4 activity and PDE4 in cultured neutrophils, and had an obviously promotive effect on gene expressions of PDE4A, 4B and 4D in later period. Luteolin had a significant inhibitory effect on neutrophils adhesion and LFA-1 expression in early stage, and had no obvious effect on MAC-1 expression. Therefore, luteolin can inhibit LFA-1 expression of neutrophils, then inhibit the adhesion of neutrophils and endothelial cells, and the mechanism is at least related with the inhibition of PDE4 activity.
基金financial support of the Beijing Natural Science Foundation of China (6112007)the Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality,China (PHR201107134)2012 Scientific Research Quality Raising Funds of Beijing University of Agriculture,China (PXM2012_014207_000010/ PXM2012_014207_000013)
文摘Our previous studies showed that the anti-inflammatory effects of Paeonia lactiflora roots extract may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inhibition on c AMP-phosphodiesterase（PDE）. To explore the anti-inflammatory effect and mechanism, the influence of gallic acid on neutrophils PDE4 activity and expression, TNF-α and IL-6 content and rat arthritis model were further studied. PDE4 activity and gene express were calculated respectively by substrate c AMP change examined with HPLC and real-time RT-PCR. The concentration of IL-6 and TNF-α in supernatant were assayed by ELISA method. Model of rat arthritis was caused by complete Freund＇s adjuvant. Results showed that gallic acid had a dose-dependent restraint on PDE4 activity of neutrophils in vitro, promoted significantly PDE4 A expression（P〈0.01）, and had no influence on the expressions of PDE4 B and 4D. However, PDE4 C expression was not detected. Gallic acid could promote IL-6 release（P〈0.05）, and inhibit TNF-α release of neutrophils（P〈0.05）. The experiment in vivo showed that gallic acid had obvious restraint on local inflammation of animal model（P〈0.05）. Therefore, the anti-inflammatory effect of gallic acid may be mediated in part through an inhibition on PDE4 activity and further an increase of IL-6 and a decrease of TNF-α of neutrophils, and this effect seemed to have no relationship with PDE4 expression.
基金supported by Rheumatology Research Foundation Innovative and Pilot grants and VA Merit Review grant(BX002858).
文摘Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis(RA)due to recently discovered neutrophil extracellular trap(NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.
文摘Selectins are carbohydrate-binding cell adhesion molecules that play a major role in the initiation of inflammatory responses. Accumulaed evidence has suggested that heparin＇s anti-inflammatory effects are mainly mediated by blocking L-or P-selectin-initiated cell adhesion. Recently, we have reported that periodate-oxidized, borohydridereduced heparin （RO-heparln） can inhibit P-selectin-mediated acute inflammation. Here we further examined the effect of RO-heparin on the adhesion of L-selectin-mediated leukocytes to vascular endothelium under flow conditions in vivo and in vitro. The results show that RO-heparin with a low anticoagulant activity can effectively reduce leucocyte roiling on thioglycoUate-induced rat mesenterlc venules and L-selectin-metadiated neutrophil roiling on TNF-α-induced human umbilical vein endothelial cells（HUVECs） under flow conditions. Our findings suggest that the effect of RO-heparin on inflammatory responses is mainly a result of its inhibiting the interaction between P- or L-selectin and its ligands. The findings also suggest that RO-heparin may be useful in preventing inflammation diseases.
基金This work was supported by the Research Fund for the Key Laboratory of Anhui Province(KLICD-2022-Z2)the Scientific Research Fund of Anhui Medical University(2011×kj083)the Scientific Research Fund of the First People's Hospital of Hefei(201642).
文摘BACKGROUND:Patients with sepsis often exhibit an acute inflammatory response,followed by an immunosuppressive phase with a poor immune response.However,the underlying mechanisms have not been fully elucidated.METHODS:We sought to comprehensively characterize the transcriptional changes in neutrophils of patients with sepsis by transcriptome sequencing.Additionally,we conducted a series of experiments,including real-time quantitative polymerase chain reaction(RT-qPCR)and flow cytometry to investigate the role of arginase-1 signaling in sepsis.RESULTS:Through the analysis of gene expression profiles,we identified that the negative regulation of T cell activation signaling was enriched,and the expression of arginase-1 was high in neutrophils from patients with sepsis.Furthermore,we conducted flow cytometry and found that the function of CD8^(+)T cells in septic patients was impaired.Moreover,neutrophils from septic patients inhibited the percentage of polyfunctional effector CD8^(+)T cells through arginase-1.Additionally,the proportions of granzyme B^(+)IFN^(-)γ^(+)CD8^(+)T and TNF^(-)α^(+)IFN^(-)γ^(+)CD8^(+)T cells increased after inhibition of arginase-1 signaling.CONCLUSION:The impaired effector function of CD8^(+)T cells could be restored by blocking arginase-1 signaling in patients with sepsis.
基金Supported by the National Natural Science Foundation of China (No.81870632)the Youth National Natural Science Foundation of China (No.81700800)the Natural Science Foundation of Shandong Province (No.ZR2017MH008)。
文摘AIM: To explore the effect of indoleamine 2,3-dioxygenase(IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus(A.fumigatus) keratitis.METHODS: C57BL/6 mice models of A.fumigatus keratitis were established by inoculating hyphae of A.fumigatus evenly on the corneas.The clinical scores and inflammatory cytokines expression were measured respectively on the 1^(st), 3^(th), 5^(th) day after infection.The 1-MT(1 mg/m L) was administered by gavage to exert an inhibitory effect on IDO during infection.The mice were divided into control group, 1-MT group, A.fumigatus(A.F.) group, and 1-MT+A.F.groups.The corneas were monitored by slit lamp microscopy, and recorded disease scores in 3 d after infection.Myeloperoxidase(MPO) assay was done to evaluate the neutrophils infiltration.Immunofluorescence staining was used to detect the recruitment of neutrophils in murine corneas.The m RNA of inflammatory cytokines was measured with reverse transcription-polymerase chain reaction(RT-PCR).RESULTS: The corneal inflammation and the clinical score reached the peak on the 3;day after the corneal infection.The m RNA of inflammatory cytokines of the A.F.group reached the highest on the 3;day after the infection accordingly.Meanwhile, the results of slit light photography indicated that inhibitors of IDO made inflammation more serious contrasted with the A.F.group on the 3;day.Besides, imunofluorescence staining and MPO indicated that 1-MT enhanced the recruitment, infiltration and chemotaxis of neutrophils obviously in contrast to the A.F.group.RT-PCR indicated that 1-MT increased the expression of CXCL-1, ICAM-1, IL-1β, and IL-8 significantly.CONCLUSION: IDO participates in the pathogenesis of A.fumigatus keratitis and plays an important role in inducing immune protection by inhibiting neutrophils-related inflammatory reaction and suppressing recruitment and chemotaxis of the neutrophils.
文摘Objective： It was known that neutrophils play an important role in ischemic-reperfusion injury. In this study we tested the effect and its mechanism of dipyfidamole on neutrophils. Methods：Hydrogen peroxide（H2O2） production by neutrophils was determined using luminol amplified chemiluminescence and the percentage of activity was calculated by observing the uninhibited peak height. Results： Dipyfidamole per se produced a concentration-dependent inhibition of H2O2 by formyl-MetleuPhe（fMLP）-stimulated neutrophils. Dipyridamole at a low concentration（0.3 μ mol · L^-1） that per se affected neutrophils only slightly, enhanced markedly the effects of adenosine on neutrophils. On the other hand, dipyfidamole did not alter the inhibitory effect of NECA（5＇ -N-ethylcarboxamidoadenosine） on neutrophils. However, propentofylline, a known inhibitor of adenosine uptake, also gotten the same result. Conclusion：Dipyfidamole inhibited the production of H2O2 by fMLP-sfimulated neutrophils. Dipyfidamole at a low concentration enhanced the inhibitory effect of adenosine on neutrophils. The mechanism involved is probably due to the effect of dipyfidamole on adenosine uptake.
文摘<span style="font-family:Verdana;">Neutrophils are the most numerous leukocyte in mammals and normally they are the first phagocyte observed in recently damaged or infected tissues. They play a key role </span><span style="font-family:Verdana;">in</span><span style="font-family:;" "=""><span><span style="font-family:Verdana;"> the innate immune responses to </span><i></i></span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> and several other microorganisms, nonetheless an exacerbated neutrophils activity can generate a harmful response to the host, therefore its turnover rate is very important to maintain the homeostasis and averts the host tissue damage. Both apoptosis followed by phagocytosis by mononuclear phagocytes (eferocytosis) and reverse transmigration have been considered the main processes for the clearance of neutrophils from injured or infected tissues. However, the interaction with </span><i></i></span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> and other microbes, as well as molecules produced by arthropod vectors such as sandflies saliva can modify the behavior of neutrophils, causing immediate lysis to prolong their life. In fact, as a result of a long course of coevolution, several microorganisms have developed skills to avoid neutrophil effector mechanisms and take advantage of neutrophil clearance pathways to promote their spread in the host’s body. </span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;">, </span><i><i><span style="font-family:Verdana;">Chlamydia pneumoniae</span></i><span></span></i><span style="font-family:Verdana;"> and </span><i><i><span style="font-family:Verdana;">Yersinia pestis</span></i><span></span></i><span style="font-family:Verdana;"> for example use the efferocytic Trojan horse process for their dissemination and immune protection, in a different way vaccinia Ankara virus and </span><i><i><span style="font-family:Verdana;">Toxoplasma gondii</span></i><span></span></i><span style="font-family:Verdana;"> exploit the neutrophil reverse transmigration for the same reason. Here we present an overview of some characteristics of neutrophils and their different destinations after interaction with several microorganisms, with an emphasis on </span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> species. It was also suggested the probable role of neutrophils reverse transmigration as another possible route for the spreading of </span><i><i><span style="font-family:Verdana;">Leishmania</span></i><span></span></i><span style="font-family:Verdana;"> in the visceral leishmaniasis.</span>
基金the National Natural Science Foundation of China(Grant number 81430099)International S&T Cooperation Program of China(Grant number 2014DFA32950)Beijing Municipal Commission of Education(Grant number 521/0101312).
文摘Objective:Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA).In this study,we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-mediated inflammation in RA.Methods:Freund's complete adjuvant-induced arthritis was used as the murine model of RA.Celastrol was intraperitoneally administrated daily after onset of the disease.The joint diameter and inflammatory score were evaluated daily during the treatment period.Myeloperoxidase (MPO) and neutrophil elastase (NE) activities were evaluated by immunohistochemical analyses.Quantitative PCR and enzyme-linked immunoabsorbent assay were used to quantify the expression of cytokines.The expression of apoptosis-related proteins Bcl-2,Bax and caspase-3 were evaluated by western blot.Results:Celastrol suppressed inflammation in joints of arthritic mice and diminished the expression of MPO and NE in the joint tissue.Celastrol significantly inhibited the expression of TNFα and IL-6 induced by LPS in neutrophils in a dose-dependent manner in vitro.Moreover,celastrol induced apoptosis of LPS-stimulated neutrophils by increasing the expression of Bax and cleaved caspase-3 while decreasing Bcl-2 expression.Conclusion:Our findings show that celastrol significantly alleviates murine arthritis by modulating the inflammatory activities of neutrophils.These results indicate that celastrol could serve as an alternative or adjunct modality for the treatment of RA.
