摘要 :
Abstract Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome and in pulmonary fibrosis. However...
展开
Abstract Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome and in pulmonary fibrosis. However, there is controversy with respect to the impact of plerixafor on neutrophil dynamics in the lung, which may affect its safety profile. In this study, we investigated the kinetics of endogenous neutrophils by direct imaging, using confocal intravital microscopy in mouse bone marrow, spleen, and lungs. Neutrophils are observed increasing their velocity and exiting the bone marrow following plerixafor administration, with a concomitant increase in neutrophil numbers in the blood and spleen, while the marginated pool of neutrophils in the lung microvasculature remained unchanged in terms of numbers and cell velocity. Use of autologous radiolabeled neutrophils and SPECT/CT imaging in healthy volunteers showed that plerixafor did not affect GM‐CSF‐primed neutrophil entrapment or release in the lungs. Taken together, these data suggest that plerixafor causes neutrophil mobilization from the bone marrow but does not impact on lung marginated neutrophil dynamics and thus is unlikely to compromise respiratory host defense both in humans and mice.
收起
摘要 :
Neutrophil extracellular traps (NETs) are a combination of DNA fibers and granular proteins, such as neutrophil elastase (NE). NETs are released in the extracellular space in response to different stimuli. Carrageenan is a sulfate...
展开
Neutrophil extracellular traps (NETs) are a combination of DNA fibers and granular proteins, such as neutrophil elastase (NE). NETs are released in the extracellular space in response to different stimuli. Carrageenan is a sulfated polysaccharide extracted from Chondrus crispus, a marine algae, used for decades in research for its potential to induce inflammation in different animal models. In this study, we show for the first time that carrageenan injection can induce NET release in a mouse model of acute peritonitis. Carrageenan induced NET release by viable neutrophils with NE and myeloperoxidase (MPO) expressed on DNA fibers. Furthermore, although this polysaccharide was able to stimulate reactive oxygen species (ROS) generation by peritoneal neutrophils, NADPH oxidase derived ROS were dispensable for NET formation by carrageenan. In conclusion, our results show that carrageenan-induced inflammation in the peritoneum of mice can induce NET formation in an ROS-independent manner. These results may add important information to the field of inflammation and potentially lead to novel anti-inflammatory agents targeting the production of NETs.
收起
摘要 :
Neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells with very defined roles in inflammation and fighting infections. However, recent advances in neutrophil research challenge...
展开
Neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells with very defined roles in inflammation and fighting infections. However, recent advances in neutrophil research challenge this limited view and demonstrate that neutrophils are highly versatile, play different roles in various pathologic scenarios, and are heterogeneous. With this, it is becoming clear that one termneutrophilis too general, and more precise nomenclature is urgently required. In this mini review, we discuss the knowns and unknowns in neutrophil terminology and highlight the critical questions that should be addressed for the establishment of clear neutrophil nomenclature.
收起
摘要 :
Abstract Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil‐platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote d...
展开
Abstract Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil‐platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStreamX (ISX) imaging flow cytometer, we were not only allowed able to detect CD15+ CD14? CD36+ ITGA2B+ NPAs in both healthy donors' (HDs) and cancer patients' bloods, but we also showed that NPAs result from the binding of platelets preferentially to low‐density neutrophils (LDNs) as opposed to normal‐density neutrophils (NDNs). By reanalyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients' derived NPAs possessed a distinct molecular signature compared to the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs‐associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans‐endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs‐associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel noninvasive blood prognostic biomarker in cancer patients with solid tumors.
收起
摘要 :
Abstract Neutrophils apply several antimicrobial strategies including degranulation, phagocytosis, the generation of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs) to fight pathogens. Iron i...
展开
Abstract Neutrophils apply several antimicrobial strategies including degranulation, phagocytosis, the generation of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs) to fight pathogens. Iron is considered to be an invaluable constituent of host immune defense and plays a dual role in immunity. It is a well‐known component of antimicrobial proteins and is a necessary microelement for pathogen survival. The aim of this study was to broaden the knowledge regarding the impact of iron on the function of neutrophils. Neutrophils from healthy blood donors and patients with mild iron‐deficiency anemia and HL‐60 cells differentiated toward granulocyte‐like cells were incubated with Fe2+, Fe3+ or holo‐transferrin (holo‐Tf). Moreover, we isolated murine neutrophils of HFE gene knockout (KO) mice and mice fed iron‐deficient, iron‐equivalent and high‐iron diets. We analyzed the release of NETs, phagocytosis, degranulation of azurophilic granules, ROS release, bactericidal activity of granulocytes against Escherichia coli and neutrophil elastase (NE) activity. We show that holo‐Tf inhibits the release of NETs stimulated by phorbol 12‐myristate 13‐acetate by inhibiting NE activity. Studies performed in mice models reveal that iron overload inhibits the release of NETs and ROS production in neutrophils isolated from HFE KO mice and mice fed a high‐iron diet. No impact of a low‐iron diet on neutrophil phagocytosis, ROS production or release of NETs was observed. Our study underscores the physiological significance of iron in neutrophil function, specifically in the release of NETs.
收起
摘要 :
Background Patients with Sweet syndrome (SS) have acute onset of cutaneous lesions with characteristic histopathology (dense and diffuse neutrophilic infiltrate, dermal edema, leukocytoclasis and no vasculitis) accompanied by syst...
展开
Background Patients with Sweet syndrome (SS) have acute onset of cutaneous lesions with characteristic histopathology (dense and diffuse neutrophilic infiltrate, dermal edema, leukocytoclasis and no vasculitis) accompanied by systemic symptoms. Sometimes, only skin lesions with classic histopathologic features are seen. Although SS is considered to be a “neutrophilic dermatosis,” lymphocytes are also seen on histological examination. Methods We evaluated the cellular infiltrate in 9 biopsies from SS lesions with routine staining and immunohistochemistry. Results Lymphocytes were present in all biopsies in variable amounts, often exceeding the number of intact neutrophils. Prominent fragmentation of neutrophils rendered some biopsies “lymphocyte‐rich” on routine histologic evaluation. Myeloperoxidase was helpful in highlighting the inconspicuous neutrophilic fragments in these cases. Lymphocytes were highlighted with immunohistochemistry, and had a CD3+, CD4+, CD20(?) immunophenotype, with rare CD8+ lymphocytes. Conclusion Awareness of the lymphocytic component of SS is important to avoid diagnostic errors, especially in subcutaneous lesions of SS, in which the lymphocytic infiltrate predominates in the upper parts of the dermis, while the typical neutrophilic infiltrate may be seen only in the deeper dermis and subcutis. The lymphocytic component may potentially help to differentiate lesions of SS from neutrophilic urticarial dermatosis, which has not been reported to contain a significant lymphocytic population.
收起
摘要 :
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 th...
展开
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.
收起
摘要 :
Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the l...
展开
Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the life quality of patients, continuous efforts have been made to create an effective strategy to prevent the occurrence of MI and reduce MI-related mortality. Numerous studies have confirmed that neutrophils play important roles in inflammation and innate immunity, which provide the first line of defense against microorganisms by producing inflammatory cytokines and chemokines, releasing reactive oxygen species, and degranulating components of neutrophil cytoplasmic granules to kill pathogens. Recently, researchers reported that neutrophils are closely related to the severity and prognosis of patients with MI, and neutrophil to lymphocyte ratio in post-MI patients had predictive value for major adverse cardiac events. Neutrophils have been increasingly recognized to exert important functions in MI. Especially, granule proteins released by neutrophil degranulation after neutrophil activation have been suggested to involve in the process of MI. This article reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Neutrophils played a crucial role throughout the process of MI, and neutrophil degranulation was the crucial step for the regulative function of neutrophils. Both neutrophils infiltrating and neutrophil degranulation take part in the injury and repair process immediately after the onset of MI. Since different granule subsets (e g. MPO, NE, NGAL, MMP‐8, MMP‐9, cathelicidin, arginase and azurocidin) released from neutrophil degranulation show different effects through diverse mechanisms in MI. In this review, we reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Myeloperoxidase (MPO); Neutrophil elastase (NE); Neutrophil gelatinase-associated lipocalin (NGAL); Matrix metalloproteinase 8 (MMP‐8); Matrix metalloproteinase 9 (MMP‐9).
收起
摘要 :
Purpose of reviewThis review will focus on in-vivo findings derived from animal models of sepsis regarding the trapping role of neutrophil extracellular traps (NETs) which is difficult to assess ex vivo. The NETotic response of ne...
展开
Purpose of reviewThis review will focus on in-vivo findings derived from animal models of sepsis regarding the trapping role of neutrophil extracellular traps (NETs) which is difficult to assess ex vivo. The NETotic response of neutrophils at sites of sterile injury or autoimmune disease is destructive as no antimicrobial advantage to the host is realized and dampening NETosis is largely beneficial. In early stages of local infection or in sepsis, the trapping function of NETs may help abscess formation and limit microbial dissemination.Recent findingsThe trapping function of NETs limits bacterial dissemination keeping an abscess from becoming bacteremic or confining tissue infection to local sites. Once containment is lost and disease has progressed, the best therapeutic approach suggested by animal studies to date is to inhibit protein arginine deiminase 4 and prevent NETosis rather than attempting to neutralize caustic NET components. Prognostic value may best be realized by taking cell free DNA, citrulllinated histones, neutrophil function and counts of immature granulocytes into consideration rather than rely on any one measure alone.SummaryThe trapping function of NETs may supercede the value of antimicrobial function in the early phases of sepsis such that degradation of the DNA backbone is contraindicated.
收起
原文获取