Neutrophil extracellular traps(NETs)formation(NETosis),is a crucial immune system mechanism mediated by neutrophils,measuring the capacity to induce NETosis is proposed as a clinical biomarker indicating the severity ...Neutrophil extracellular traps(NETs)formation(NETosis),is a crucial immune system mechanism mediated by neutrophils,measuring the capacity to induce NETosis is proposed as a clinical biomarker indicating the severity of COVID-19 and long COVID.Azvudine(FNC),has shown efficacy in treating SARS-CoV-2 infection and potential for alleviating inflammation.However,the molecular mechanism underlying its anti-inflammatory effects has not been extensively investigated.Therefore,a series of experiments were conducted on SARS-CoV-2 infected rhesus macaques(RMs)to investigate the anti-inflammatory effects of FNC.The experiments involved HE staining,mass spectrometry-based proteomics,validation experiments conducted in vivo using RMs tissues and in vitro differentiation of HL-60 cells.Additionally,interaction investigations were carried out utilizing LiP-MS,CETSA,Co-IP along with molecular docking.The results demonstrated that FNC treatment effectively alleviated neutrophil infiltration and attenuated inflammatory injury following infection.In addition to exhibiting antiviral effects,FNC treatment exhibited a reduction in inflammation-associated proteins and pathways such as myeloperoxidase(MPO)and the formation of NETs,respectively.Validation experiments confirmed the impact of FNC on regulating NETs formation,interaction experiments suggested that MPO may serves as a therapeutic target.The multifaceted properties of FNC,including its antiviral and anti-inflammatory characteristics,highlight the therapeutic potential in diseases associated with NETosis,particularly those involving concurrent SARS-CoV-2 infection,providing insights for drug development targeting MPO and NETosis-associated diseases.展开更多
Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections.Thus,inflammasomes participate in many conditions,such as acne.Recently,it was shown that NETosis,a type of neutroph...Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections.Thus,inflammasomes participate in many conditions,such as acne.Recently,it was shown that NETosis,a type of neutrophil cell death,is induced by bacterial infection and is involved in inflammatory diseases such as delayed wound healing in patients with diabetes.However,the relationship between inflammasomes and NETosis in the pathogenesis of inflammatory diseases has not been well studied.In this study,we determined whether NETosis is induced in P.acnes-induced skin inflammation and whether activation of the nucleotide-binding domain,leucine-rich family,and pyrin domain-containing-3(NLRP3)inflammasome is one of the key factors involved in NETosis induction in a mouse model of acne skin inflammation.We found that NETosis was induced in P.acnes-induced skin inflammation in mice and that inhibition of NETosis ameliorated P.acnes-induced skin inflammation.In addition,our results demonstrated that inhibiting inflammasome activation could suppress NETosis induction in mouse skin.These results indicate that inflammasomes and NETosis can interact with each other to induce P.acnes-induced skin inflammation and suggest that targeting NETosis could be a potential treatment for inflammasome-mediated diseases as well as NETosis-related diseases.展开更多
Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression.In response to inflammatory stimuli,neutrophils become activated,releasing neutrophils extracel...Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression.In response to inflammatory stimuli,neutrophils become activated,releasing neutrophils extracellular traps(NETs)for the capture and eradication of pathogens,a phenomenon termed NETosis.With a deeper understanding of NETs,there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies,especially concerning tumor reactions to chemotherapy,radiation therapy(RT),and immunotherapy.This review summarizes the roles of NETs in the tumor microenvironment(TME)and their mechanisms of neutrophil involvement in the host defense.Additionally,it elucidates the mechanisms through which NETs promote tumor progression and their role in cancer treatment resistance,highlighting their potential as promising therapeutic targets in cancer treatment and their clinical applicability.展开更多
NETosis is a regulated form of neutrophil cell death that contributes to the host defense against pathogens and was linked to various diseases soon after its first description in 2004.During NETosis,neutrophils releas...NETosis is a regulated form of neutrophil cell death that contributes to the host defense against pathogens and was linked to various diseases soon after its first description in 2004.During NETosis,neutrophils release neutrophil extracellular traps(NETs),which can capture and kill bacteria and other pathogens to prevent them from spreading.Although substantial progress has been made in our understanding of NETosis,the precise mechanism underlying NETosis is still a matter of debate.Research continues to elucidate the molecular pathways involved in NETosis.In recent years,interactions with the complement and coagulation systems have become increasingly apparent.Activated complement proteins can stimulate NET formation,and NETs,in turn,can serve as a platform for complement activation.In addition,NETs can act as a scaffold for thrombus formation during coagulation.While crosstalk between the coagulation and complement systems has been previously described,NETosis appears to be a third important player in this consortium to protect the host against pathogens.This review summarizes our current knowledge on the mutual interactions between NETosis,the complement system and the coagulation system,with an emerging description of their complex triangular relationship.展开更多
Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we ...Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we showed that pancreatic melatonin level is associated with patients'survival.In PAAD mice models,melatonin supplementation suppressed tumor growth,while blockade of melatonin pathway exacerbated tumor progression.This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils(TANs),and TANs depletion reversed effects of melatonin.Melatonin induced TANs infiltration and activation,therefore induced cell apoptosis of PAAD cells.Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells.Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation.Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype,with increased neutrophil extracellular traps(NETs)causing tumor cell apoptosis through cell-to-cell contact.Proteomics analysis revealed that this reactive oxygen species(ROS)-mediated inhibition was fueled by fatty acid oxidation(FAO)in neutrophils,while FAO inhibitor abolished the anti-tumor effect.Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration.CXCL2,or TANs,combined with NET marker,can better predict patients'prognosis.Collectively,we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.展开更多
It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)ago...It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)agonists are associated with a greater risk of diabetes.However,the role of GnRH in diabetic wound healing is unclear.We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing.A mouse model of diabetes was established using five injections with streptozotocin.Mice with blood glucose levels>250 mg/dL were then used in the experiments.GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice.In contrast,GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing.The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients.In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate(PMA)-induced NETosis in mouse and human neutrophils.Furthermore,GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis,which were increased by GnRH treatment.These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds.Thus,inhibition of GnRH might be a novel treatment of diabetic foot ulcers.展开更多
Regulated cell death(RCD)is essential for maintaining cell homeostasis and preventing diseases.Besides classical apoptosis,several novel nonapoptotic forms of RCD including NETosis,pyroptosis,ferroptosis,and cuproptos...Regulated cell death(RCD)is essential for maintaining cell homeostasis and preventing diseases.Besides classical apoptosis,several novel nonapoptotic forms of RCD including NETosis,pyroptosis,ferroptosis,and cuproptosis have been reported and are increasingly being implicated in various cancers and inflammation.Disulfiram(DSF),an aldehyde dehydrogenase inhibitor,has been used clinically for decades as an anti-alcoholic drug.New studies have shown that DSF possesses potent anti-inflammatory and anti-cancer effects by regulating these new types of RCD.Here,we summarize the mechanisms and discuss the potential application of DSF in the treatment of cancers and inflammatory diseases.展开更多
Neutrophils, crucial players in the effector phase of the immune response, are recognized as important mediators of both innate and adaptive immune responses. Through the production of pro- and anti-inflammatory cytok...Neutrophils, crucial players in the effector phase of the immune response, are recognized as important mediators of both innate and adaptive immune responses. Through the production of pro- and anti-inflammatory cytokines, they modulate the function of T and other lymphoid cells. Countless reports have highlighted the importance of these cells as efficient antimicrobial agents and annotated their involvement in the pathology of infectious and noninfectious diseases. The development of modern, sophisticated technologies has allowed the study of the functions of these cells in clinical settings. These advanced technologies include fluorescence-activated cell sorters, confocal microscopy, automated cell image analyzers, and live cell analysis instruments. Unfortunately, the cost of these modern instruments, maintenance, reagents, and the need for qualified technicians prohibit their use in low-income laboratories and universities in developing countries. With this in mind, we propose a series of basic tests that can be used in low-input clinical laboratories and universities to evaluate the function of neutrophils in health and disease. Our methodology allows us to assess in a practical and low-cost manner the functions of neutrophils in the phagocytic process, including opsonization, ingestion, ROI production (NBT reduction), myeloperoxidase content, phagosome-lysosome fusion, microbicidal activity, and NET production. Thus, under a disadvantageous ambiance, this may guide physicians in deciding whether a patient’s illness involves phagocytic defects without imposing a heavy financial burden.Graphical Abstract[-rId13-]展开更多
Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pat...Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases.展开更多
基金supported by National Nature Science Foundation of China(No.82151525).
文摘Neutrophil extracellular traps(NETs)formation(NETosis),is a crucial immune system mechanism mediated by neutrophils,measuring the capacity to induce NETosis is proposed as a clinical biomarker indicating the severity of COVID-19 and long COVID.Azvudine(FNC),has shown efficacy in treating SARS-CoV-2 infection and potential for alleviating inflammation.However,the molecular mechanism underlying its anti-inflammatory effects has not been extensively investigated.Therefore,a series of experiments were conducted on SARS-CoV-2 infected rhesus macaques(RMs)to investigate the anti-inflammatory effects of FNC.The experiments involved HE staining,mass spectrometry-based proteomics,validation experiments conducted in vivo using RMs tissues and in vitro differentiation of HL-60 cells.Additionally,interaction investigations were carried out utilizing LiP-MS,CETSA,Co-IP along with molecular docking.The results demonstrated that FNC treatment effectively alleviated neutrophil infiltration and attenuated inflammatory injury following infection.In addition to exhibiting antiviral effects,FNC treatment exhibited a reduction in inflammation-associated proteins and pathways such as myeloperoxidase(MPO)and the formation of NETs,respectively.Validation experiments confirmed the impact of FNC on regulating NETs formation,interaction experiments suggested that MPO may serves as a therapeutic target.The multifaceted properties of FNC,including its antiviral and anti-inflammatory characteristics,highlight the therapeutic potential in diseases associated with NETosis,particularly those involving concurrent SARS-CoV-2 infection,providing insights for drug development targeting MPO and NETosis-associated diseases.
基金supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(Grant No:HR21C1003)Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT,and Future Planning(2023R1A2C3002835).
文摘Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections.Thus,inflammasomes participate in many conditions,such as acne.Recently,it was shown that NETosis,a type of neutrophil cell death,is induced by bacterial infection and is involved in inflammatory diseases such as delayed wound healing in patients with diabetes.However,the relationship between inflammasomes and NETosis in the pathogenesis of inflammatory diseases has not been well studied.In this study,we determined whether NETosis is induced in P.acnes-induced skin inflammation and whether activation of the nucleotide-binding domain,leucine-rich family,and pyrin domain-containing-3(NLRP3)inflammasome is one of the key factors involved in NETosis induction in a mouse model of acne skin inflammation.We found that NETosis was induced in P.acnes-induced skin inflammation in mice and that inhibition of NETosis ameliorated P.acnes-induced skin inflammation.In addition,our results demonstrated that inhibiting inflammasome activation could suppress NETosis induction in mouse skin.These results indicate that inflammasomes and NETosis can interact with each other to induce P.acnes-induced skin inflammation and suggest that targeting NETosis could be a potential treatment for inflammasome-mediated diseases as well as NETosis-related diseases.
基金supported by the National Natural Science Foundation of China(Nos.82072930,82222055,32270971,82001822)Guangzhou Science and Technology Bureau(No.202201020576)+1 种基金111 project(No.B20056)the Guangdong Province Outstanding Youth Award(No.2021B1515020066).
文摘Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression.In response to inflammatory stimuli,neutrophils become activated,releasing neutrophils extracellular traps(NETs)for the capture and eradication of pathogens,a phenomenon termed NETosis.With a deeper understanding of NETs,there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies,especially concerning tumor reactions to chemotherapy,radiation therapy(RT),and immunotherapy.This review summarizes the roles of NETs in the tumor microenvironment(TME)and their mechanisms of neutrophil involvement in the host defense.Additionally,it elucidates the mechanisms through which NETs promote tumor progression and their role in cancer treatment resistance,highlighting their potential as promising therapeutic targets in cancer treatment and their clinical applicability.
基金This work was supported in part by the Dutch Technology Foundation STW.
文摘NETosis is a regulated form of neutrophil cell death that contributes to the host defense against pathogens and was linked to various diseases soon after its first description in 2004.During NETosis,neutrophils release neutrophil extracellular traps(NETs),which can capture and kill bacteria and other pathogens to prevent them from spreading.Although substantial progress has been made in our understanding of NETosis,the precise mechanism underlying NETosis is still a matter of debate.Research continues to elucidate the molecular pathways involved in NETosis.In recent years,interactions with the complement and coagulation systems have become increasingly apparent.Activated complement proteins can stimulate NET formation,and NETs,in turn,can serve as a platform for complement activation.In addition,NETs can act as a scaffold for thrombus formation during coagulation.While crosstalk between the coagulation and complement systems has been previously described,NETosis appears to be a third important player in this consortium to protect the host against pathogens.This review summarizes our current knowledge on the mutual interactions between NETosis,the complement system and the coagulation system,with an emerging description of their complex triangular relationship.
基金partially supported by the Research Council of the University of Hong Kong(project codes:104004092 and 104004460,China)the Wong's donation(project code:200006276,HKSAR)+4 种基金a donation from the Gaia Family Trust of New Zealand(project code:200007008)the Research Grants Committee(RGC)of Hong Kong,HKSAR(Project Codes:740608,766211,17152116 and 17121419,China)the Health and Medical Research Fund(Project code:15162961 and 16172751,HKSAR)the Enhanced New Staff Start-up Fund(Project code:204610519,HKSAR)the Pre-emptive Retention Fund(Project code:202007002,HKSAR)。
文摘Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we showed that pancreatic melatonin level is associated with patients'survival.In PAAD mice models,melatonin supplementation suppressed tumor growth,while blockade of melatonin pathway exacerbated tumor progression.This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils(TANs),and TANs depletion reversed effects of melatonin.Melatonin induced TANs infiltration and activation,therefore induced cell apoptosis of PAAD cells.Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells.Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation.Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype,with increased neutrophil extracellular traps(NETs)causing tumor cell apoptosis through cell-to-cell contact.Proteomics analysis revealed that this reactive oxygen species(ROS)-mediated inhibition was fueled by fatty acid oxidation(FAO)in neutrophils,while FAO inhibitor abolished the anti-tumor effect.Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration.CXCL2,or TANs,combined with NET marker,can better predict patients'prognosis.Collectively,we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.
基金This study was supported by the National Research Foundation of Korea grant funded by the Korean government(MSIP)(No.2011-0030043(SRC)),(2017M3A9F7079339)the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT,and Future Planning(2018R1A2B3009008).
文摘It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)agonists are associated with a greater risk of diabetes.However,the role of GnRH in diabetic wound healing is unclear.We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing.A mouse model of diabetes was established using five injections with streptozotocin.Mice with blood glucose levels>250 mg/dL were then used in the experiments.GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice.In contrast,GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing.The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients.In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate(PMA)-induced NETosis in mouse and human neutrophils.Furthermore,GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis,which were increased by GnRH treatment.These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds.Thus,inhibition of GnRH might be a novel treatment of diabetic foot ulcers.
基金This work was supported by grants from the National Natural Science Foundation of China(81770158)Guangdong Science and Technology Project(No.2020A0505100042)the Pearl River S&T Nova Program of Guangzhou,China(No.201906010002)。
文摘Regulated cell death(RCD)is essential for maintaining cell homeostasis and preventing diseases.Besides classical apoptosis,several novel nonapoptotic forms of RCD including NETosis,pyroptosis,ferroptosis,and cuproptosis have been reported and are increasingly being implicated in various cancers and inflammation.Disulfiram(DSF),an aldehyde dehydrogenase inhibitor,has been used clinically for decades as an anti-alcoholic drug.New studies have shown that DSF possesses potent anti-inflammatory and anti-cancer effects by regulating these new types of RCD.Here,we summarize the mechanisms and discuss the potential application of DSF in the treatment of cancers and inflammatory diseases.
文摘Neutrophils, crucial players in the effector phase of the immune response, are recognized as important mediators of both innate and adaptive immune responses. Through the production of pro- and anti-inflammatory cytokines, they modulate the function of T and other lymphoid cells. Countless reports have highlighted the importance of these cells as efficient antimicrobial agents and annotated their involvement in the pathology of infectious and noninfectious diseases. The development of modern, sophisticated technologies has allowed the study of the functions of these cells in clinical settings. These advanced technologies include fluorescence-activated cell sorters, confocal microscopy, automated cell image analyzers, and live cell analysis instruments. Unfortunately, the cost of these modern instruments, maintenance, reagents, and the need for qualified technicians prohibit their use in low-income laboratories and universities in developing countries. With this in mind, we propose a series of basic tests that can be used in low-input clinical laboratories and universities to evaluate the function of neutrophils in health and disease. Our methodology allows us to assess in a practical and low-cost manner the functions of neutrophils in the phagocytic process, including opsonization, ingestion, ROI production (NBT reduction), myeloperoxidase content, phagosome-lysosome fusion, microbicidal activity, and NET production. Thus, under a disadvantageous ambiance, this may guide physicians in deciding whether a patient’s illness involves phagocytic defects without imposing a heavy financial burden.Graphical Abstract[-rId13-]
基金supported by the USA National Institutes of Health Grant R01-HL-079669USA National Institutes of Health Center Grant P50-GM-53789a USA VA Merit Award
文摘Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases.
