Journal of Leukocyte Biology最新文献

{"title":"Natural antibodies as frontline helpers in bacterial clearance.","authors":"Bruna Araujo David, Paul Kubes","doi":"10.1093/jleuko/qiaf028","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf028","url":null,"abstract":"","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 5","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toll-like receptor 8 activation induces a neutrophil inflammatory phenotype: therapeutic implications for the utility of toll-like receptor 8 inhibition.","authors":"Angelika Schmidt, Matthew Coughlin, Michelle D Catalina, Melinda Przetak, Irina Kalatskaya, Matthew Studham, Jamie Shaw, Andrew T Bender, Fatima Strand","doi":"10.1093/jleuko/qiaf036","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf036","url":null,"abstract":"<p><p>Excessive activation of toll-like receptor 7 and 8 (TLR7/8) plays a role in the pathogenesis of autoimmune diseases and is associated with negative outcomes from viral infections. Neutrophil activation is highly inflammatory and mediates tissue damage. We explored the effects of TLR7/8 activation in neutrophils to better understand neutrophil biology and evaluate the therapeutic utility of TLR7/8 inhibitors in indications where neutrophils contribute to disease pathogenesis. We found that TLR8, but not TLR7, is active in human neutrophils. TLR8 activation led to increased interleukin-8 (IL-8) secretion and resulted in significant changes in gene expression, as determined by RNA sequencing, with increased expression of genes encoding cytokines and other inflammatory mediators. Type I interferon (IFN) also induced gene expression changes distinct from those induced by TLR8. Additionally, neutrophil extracellular traps (NET) formation and DNA release, or NETosis, was induced by TLR8 activation in IFN-primed neutrophils. Treatment with a TLR7/8 inhibitor (CMPD2) effectively blocked IL-8 secretion and NETosis. In a Phase II clinical trial in COVID-19 pneumonia, TLR7/8 inhibition with enpatoran affected neutrophil counts. Expression of NFKBIZ was induced by TLR8 in neutrophils in vitro and found to also be reduced by enpatoran in patients with COVID-19, suggesting it may be useful as a marker for TLR8-activated neutrophils and for identifying candidate diseases and patients that may benefit from treatment with a TLR7/8 inhibitor. Overall, our findings provide new insights into TLR8 and neutrophil biology that have therapeutic implications in autoimmune diseases and immune-mediated inflammation.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 5","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early neutrophil responses are potential biomarkers to predict severe COVID-19 in adults.","authors":"Ananya Singh, Nurhidayah Binte Mohamed Yazid, Raika Francesca Morales, Keisuke Ejima, Po Ying Chia, Siew Wai Fong, Lisa F P Ng, Laurent Renia, David Chien Lye, Lousia Jin Sun, Seow Yen Tan, Louis Yi Ann Chai, Shirin Kalimuddin, Barnaby Edward Young, Tsin Wen Yeo, Andrew Teo","doi":"10.1093/jleuko/qiaf035","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf035","url":null,"abstract":"<p><p>In the early COVID-19 pandemic, the strain on healthcare facilities highlighted the need for reliable biomarkers to predict progression to severe COVID-19. Neutrophils, the most abundant leukocytes in circulation, are early defenders against pathogens. In a Singaporean adult cohort, early neutrophil mediators were assessed for their suitability as prognostic biomarkers of COVID-19 complications. Plasma levels of myeloperoxidase (MPO), elastase, soluble urokinase plasminogen activator receptor (suPAR), and soluble suppressor of tumorigenicity 2 (sST2) in 35 nonsevere and 14 severe cases were measured twice, 2 to 7 d apart after hospitalization. Nineteen controls were included. The levels of MPO, elastase, suPAR, and sST2 were significantly higher in patients with severe COVID-19 compared with those with mild and healthy controls. At baseline sampling, MPO and suPAR predicted severe COVID-19 and had AUROCs of 0.76 and 0.87, respectively. MPO and suPAR at cut-off values of 26.41 ng/mL and 3.19 ng/mL, respectively showed approximately 71% sensitivity and 81% to 84% specificity to differentiate severe COVID-19. In contrast, elastase and neutrophil counts were less predictive of severe disease. In adult COVID-19, MPO and suPAR may be reliable prognostic biomarkers of severe disease during acute COVID-19. Further validation of these markers in a larger cohort and in other infectious diseases is warranted.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 5","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired LPS tolerance in monocytes of coronary atherosclerosis patients is associated with the intermediate subset.","authors":"Nikita G Nikiforov, Yegor S Chegodaev, Svetlana S Verkhova, Elena A Pudova, Mikhail A Popov, Anna V Tvorogova, Alexander D Zhuravlev, Ruslan A Maslennikov, Anastasiya V Snezhkina, Anna V Kudryavtseva, Yegor E Yegorov, Andrey V Omelchenko, Daria D Borodko, Dmitry I Zybin, Dmitry V Shumakov, Alexander N Orekhov","doi":"10.1093/jleuko/qiaf060","DOIUrl":"10.1093/jleuko/qiaf060","url":null,"abstract":"<p><p>Endotoxin tolerance in monocytes is a mechanism that reduces the secretion of inflammatory cytokines upon repeated pathogen exposure, thereby protecting tissues from hyperinflammation. Previously, we demonstrated that monocytes from patients with asymptomatic carotid atherosclerosis exhibit impaired LPS tolerance. In this study, we aimed to investigate monocyte tolerance impairments in coronary atherosclerosis in greater detail. The study included 46 male patients with ischemic heart disease, divided into two groups based on coronary angiography results with and without coronary atherosclerosis. CD14 + monocytes were isolated from patients' blood and subjected to LPS stimulation on days 1 and 7 of culture. Transcriptomic analysis of monocytes was conducted. Monocyte subpopulations were assessed and sorted based on CD14 and CD16 expression. Patients with coronary atherosclerosis exhibited disrupted inflammatory responses in monocytes, characterized by elevated basal and LPS-induced IL-1β secretion. These patients demonstrated impaired LPS tolerance, as evidenced by increased CCL2 secretion upon repeated stimulation. Transcriptomic analysis revealed upregulation of inflammatory genes, particularly those associated with minor CD16 + monocyte subpopulations. The proportions of non-classical and intermediate monocytes were elevated in patients with atherosclerosis, with IL-1β and CCL2 secretion levels correlating predominantly with the intermediate monocyte subset. Functional analysis revealed that non-classical monocytes from healthy donors developed stable endotoxin tolerance. In contrast, intermediate and classical monocytes from some donors exhibited a non-tolerant response to LPS, as evidenced by secretion of IL-1β, IL-6, and CCL2. The differentiation of classical monocytes into intermediate monocytes may play a key role in the impaired endotoxin tolerance observed in atherosclerosis.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-tumor necrosis factor therapy in the treatment of systemic autoinflammatory diseases: the responses of innate immune cells.","authors":"Shuyi Wang, Rufei Xiao, Yibo Chen, Yishan Ye, Tianzhen He, Yang Yang, Xin Chen, Chon-Kit Chou","doi":"10.1093/jleuko/qiaf026","DOIUrl":"10.1093/jleuko/qiaf026","url":null,"abstract":"<p><p>Systemic autoinflammatory diseases are rare conditions resulting from dysregulation of the innate immune system, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most systemic autoinflammatory diseases are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-tumor necrosis factor therapy is widely used in the clinical management of systemic autoinflammatory diseases. Tumor necrosis factor inhibitors block the interaction of tumor necrosis factor with its 2 receptors, tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2. These inhibitors primarily target soluble tumor necrosis factor, which mainly binds to tumor necrosis factor receptor 1, exerting anti-inflammatory effects. Interestingly, tumor necrosis factor inhibitors also affect transmembrane tumor necrosis factor, which engages tumor necrosis factor receptor 2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. Tumor necrosis factor inhibitors also promote the release of soluble tumor necrosis factor receptor 2, which neutralizes circulating tumor necrosis factor. Some agents targeting tumor necrosis factor receptor 2 can even act as agonists, triggering reverse signaling by binding to transmembrane tumor necrosis factor. While effective, prolonged use of tumor necrosis factor inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of tumor necrosis factor receptors. A more thorough understanding of the mechanisms underlying the action of tumor necrosis factor inhibitors is required to develop a more effective and safer treatment for systemic autoinflammatory diseases. This article reviews current studies on the role of the innate immune system in systemic autoinflammatory disease pathogenesis, the impact of anti-tumor necrosis factor therapy on innate immune cells, and perspectives on developing improved agents targeting tumor necrosis factor or its receptors.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD73 promotes the maturation of murine NK cells and their survival in the tumor microenvironment.","authors":"Brian Parra-Tello, Moira García-Gómez, Eva Rekus-Polanska, Felipe Malgue, Sebastián Charlín, Andrés Hernández-Oliveras, Javiera Reyes-Alvarez, Mario Rosemblatt, Andreas Lundqvist, Alvaro Lladser, María Rosa Bono, Daniela Sauma","doi":"10.1093/jleuko/qiaf011","DOIUrl":"10.1093/jleuko/qiaf011","url":null,"abstract":"<p><p>Natural Killer (NK) cells are crucial in recognizing and eliminating tumor cells, making them pivotal in antitumor responses. Adenosine, the product of ATP hydrolysis mediated by CD39 and CD73 ectonucleotidases, has been reported to reduce the proliferation and maturation of NK cells. In this study, we investigate the expression of CD73 in NK cells and its impact on maturation, phenotype, survival, and function. Our findings reveal that while splenic NK cells express minimal levels of CD73, its expression is induced upon activation and in the tumor microenvironment upon adoptive transfer to tumor-bearing mice. Notably, within the tumor microenvironment, CD73 expression in NK cells correlates with elevated levels of PD-L1 and CD226. Accordingly, analysis of human melanoma datasets uncovers a subset of immature tumor-infiltrating NK cells expressing CD73. To further understand the role of CD73 on NK cells, we used a CD73 knockout (KO) murine model and observed that CD73-deficient NK cells display a more immature phenotype and heightened proliferative activity than wild-type (WT) NK cells. Additionally, CD73-deficient NK cells exhibit elevated levels of P2X7R and reduced CD39 expression, suggesting an increased susceptibility to ATP-induced death. Following adoptive transfer to tumor-bearing mice, CD73KO NK cells are present at a lower frequency but demonstrate similar control over tumor growth compared with WT NK cells. In conclusion, our study demonstrates the upregulation of CD73 in NK cells infiltrating tumors and underscores its role as a checkpoint regulating the functional maturation of NK cells.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient generation of human dendritic cells from induced pluripotent stem cell by introducing a feeder-free expansion step for hematopoietic progenitors.","authors":"Zahra Elahi, Vanta Jameson, Magdaline Sakkas, Suzanne Kathryn Butcher, Justine D Mintern, Kristen Jane Radford, Christine Anne Wells","doi":"10.1093/jleuko/qiaf045","DOIUrl":"10.1093/jleuko/qiaf045","url":null,"abstract":"<p><p>Dendritic cells (DCs) are rare innate immune cells that are essential regulators of antitumor, antiviral, and vaccine responses by the adaptive immune system. Conventional DCs, particularly the cDC1 subset, are most desired for DC-based immunotherapies, however, it can be difficult to isolate sufficient numbers of primary cells from patients. The most common alternate sources of DC are ex vivo monocyte-derived DC, although patient-derived monocytes are often dysfunctional. Induced pluripotent stem cells (iPSC) offer a promising solution, providing an opportunity for in vitro generating DCs that are suitable for allogenic off-the-shelf batch-manufactured cells. Here, we developed an in vitro protocol designed to maximize the yield of iPSC-derived DC progenitors, with the specific goal of generating cDC1-like cells. The iPSC-DCs subsets generated by our method could be partitioned by cell surface phenotypes of cDC1, cDC2, and DC3, but they were most transcriptionally similar to monocyte-derived DC (MoDC). Stimulated iPSC-DCs generated proinflammatory cytokines, expressed migratory chemokine receptors including CCR7, upregulated co-stimulatory molecules, and induced the proliferation of CD4/CD8 T-cells. Altogether these data indicate that iPSC-derived DCs have the potential to traffic through lymphatic endothelium and engage productively with T-cells. This method offers a promising step toward an expandable source of allogeneic human DCs for future applications.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep phenotyping of human neutrophils in whole blood using a 33-color spectral flow cytometry panel.","authors":"Vanessa Krémer, Marion Rambault, Sandrine Schmutz, Nicolas Montcuquet, Pierre Bruhns, Luc de Chaisemartin, Friederike Jönsson","doi":"10.1093/jleuko/qiaf049","DOIUrl":"10.1093/jleuko/qiaf049","url":null,"abstract":"<p><p>Neutrophils are the most abundant leukocytes in the circulation and critical players in host defense and inflammation. They respond rapidly to numerous biological, chemical, and physical stimuli, making it challenging to characterize their steady-state phenotypes, activation states, and subsets in an unbiased and precise manner. To address this problem, we designed a 33-color spectral flow cytometry panel for the deep profiling of unprocessed neutrophils in human blood. This panel allows the profiling of neutrophil phenotypes related to activation, immune modulation, granule release, ontogeny, phagocytic capacity, and migration, in addition to monitoring all major human leukocyte populations. We validated the panel using whole blood stimulations that induce distinct phenotypic shifts in the neutrophil population. This optimized spectral flow cytometry panel allows comprehensive immune profiling of the functional heterogeneity of human blood neutrophils and is suitable for longitudinal or exploratory analysis of neutrophil dynamics and activation states in clinical cohorts.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The release of NETs during SFTSV infection downregulates the specific inflammatory factors that lead to liver and spleen damage.","authors":"Xuewen Ji, Xinyi Yu, Zihan Xiao, Ruonan Zhang, Zihan Wu, Xinrui Zhang, Chunhui Wang, Jin Zhu, Ye Yang, Tingting Zhou","doi":"10.1093/jleuko/qiaf053","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf053","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome is a life-threatening condition that has been the focus of attention in recent years. It is primarily caused by uncontrolled replication of a novel Bunyavirus and an intense pro-inflammatory response. NETosis is a form of cell death initiated by neutrophils, involving the formation of neutrophil extracellular traps. These NETs are composed of DNA fibers or nuclear chromatin that trap cytoplasmic granule proteins and histones in a meshwork to capture and eliminate pathogens.Our investigation delved into single-cell sequencing data from SFTS patients, revealing that SFTSV can trigger NETosis in both cellular and animal models. Furthermore, we examined the impact of NETs on Thp-1 cells through transcriptome sequencing and evaluated tissues in infected animal models, unveiling a significant down-regulation of specific inflammatory factors. By integrating previous research, we propose a hypothesis that the reduction of these inflammatory factors hinders the occurrence of immune responses and the process of organ repair, thereby causing tissue damage.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifaceted roles of neutrophils in cardiac disease.","authors":"Samantha M Morrissey, Logan G Kirkland, Tasha K Phillips, Rebecca D Levit, Alex Hopke, Brian C Jensen","doi":"10.1093/jleuko/qiaf017","DOIUrl":"10.1093/jleuko/qiaf017","url":null,"abstract":"<p><p>Neutrophils, the most abundant leukocytes in human blood, have long been recognized as critical first responders in the innate immune system's defense against pathogens. Some of the more notable innate antimicrobial properties of neutrophils include generation of superoxide free radicals like myeloperoxidase, production of proteases that reshape the extracellular matrix allowing for easier access to infected tissues, and release of neutrophil extracellular traps, extruded pieces of DNA that ensnare bacterial and fungi. These mechanisms developed to provide neutrophils with a vast array of specialized functions to provide the host defense against infection in an acute setting. However, emerging evidence over the past few decades has revealed a far more complex and nuanced role for these neutrophil-driven processes in various chronic conditions, particularly in cardiovascular diseases. The pathophysiology of cardiac diseases involves a complex interplay of hemodynamic, neurohumoral, and inflammatory factors. Neutrophils, as key mediators of inflammation, contribute significantly to this intricate network. Their involvement extends far beyond their classical role in pathogen clearance, encompassing diverse functions that can both exacerbate tissue damage and contribute to repair processes. Here, we consider the contributions of neutrophils to myocardial infarction, heart failure, cardiac arrhythmias, and nonischemic cardiomyopathies. Understanding these complex interactions is crucial for developing novel therapeutic strategies aimed at modulating neutrophil functions in these highly morbid cardiac diseases.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}