Journal of Leukocyte Biology最新文献

{"title":"Actin regulation of neutrophil effector mechanisms in health and disease.","authors":"Noelle Pisacano, Rebecca A Evans, Abigail S Nutley, Katharine M Lodge, Maria Prendecki","doi":"10.1093/jleuko/qiaf142","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf142","url":null,"abstract":"<p><p>Neutrophils are central to immune responses in health and disease, and their ability to deform correlates with their functional responses. In health, reorganisation of the neutrophil cytoskeleton allows neutrophils to carry out their effector mechanisms. However, in the disease state, dysregulation of neutrophil cytoskeletal properties results in disruption of neutrophil structural integrity, in turn altering their immune response capabilities. We outline how actin and actin polymerisation are essential for cell processes, the role of actin in neutrophil function, and how disruption of actin can lead and contribute to a range of disease pathogeneses.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251307","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":"Human CD24+CD38+ regulatory B cells promote Pro-resolving Macrophage Function through the synergistic effect of IL-10 and PD-L1.","authors":"Elaheh Dalir Abdolahinia, Elizabeth M Horta, Takumi Memida, Guoqin Cao, Shengyuan Huang, Sunniva Ruiz, Satoru Shindo, Shin Nakamura, Jiang Lin, Saynur Vardar, Toshihisa Kawai, Xiaozhe Han","doi":"10.1093/jleuko/qiaf141","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf141","url":null,"abstract":"<p><p>Regulatory B cells (Bregs), specifically the CD24⁺CD38⁺ phenotype, are known for their capacity to reduce inflammation by releasing interleukin 10(IL-10). However, their potential role in regulating inflammation through macrophage differentiation is not well understood. This study investigates how CD24⁺CD38⁺ regulatory B cells modulate the differentiation and function of pro-resolving macrophages through programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) interactions and IL-10 secretion. Human CD24⁺CD38⁺ B cells were isolated from peripheral blood and co-cultured with THP-1-derived macrophages. Recombinant IL-10/PD-L1 and neutralizing antibodies were used to conduct gain and loss-of-function studies. Flow cytometry, quantitative PCR, and mass spectrometry were used to evaluate macrophage polarization, efferocytosis activity, and pro-resolving lipid mediator production. After co-culture, M2 polarization, PD-1 expression, and efferocytosis activity were increased significantly. Inhibition of either IL-10 or PD-L1 pathway reduced M2 macrophage differentiation and functional activity. Co-culture of macrophages with CD24⁺CD38⁺ B cells enhanced the production of pro-resolving lipid mediators, particularly 12-HEPE and RvD5 through IL-10 secretion and PD-L1/PD-1 ligation. These findings reveal a novel mechanism by which human CD24⁺CD38⁺ regulatory B cells promote macrophage-mediated resolution of inflammation through IL-10 secretion and PD-L1/PD-1 ligation. By exploring how these regulatory pathways influence macrophage biology, we ultimately aim to uncover novel therapeutic targets for enhancing inflammation resolution in chronic inflammatory diseases.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244595","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":"Lyn expression in macrophages promotes TLR activation and restricts proliferation in an isoform-independent manner.","authors":"Anders J Lindstedt, Joseph T Greene, Yingzheng Xu, Jesse W Williams, Tanya S Freedman","doi":"10.1093/jleuko/qiaf140","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf140","url":null,"abstract":"<p><p>Toll-like receptor (TLR) signaling is vital for antimicrobial macrophage function, and its dysregulation is associated with diseases such as lupus, multiple sclerosis, pulmonary fibrosis, and cancer. The Src-family kinase Lyn may have net activating or inhibitory effects on TLR signaling, yet distinct functions of the Lyn splice variants LynA and LynB in TLR signaling have not been investigated. We used isoform-specific Lyn knockout mice (LynAKO and LynBKO) to interrogate the contribution of each isoform to TLR signaling in bone-marrow-derived macrophages. Bulk RNA sequencing and cytokine analyses revealed that complete Lyn deficiency (LynKO) dampened TLR4- and TLR7-induced inflammatory gene expression and production of tumor necrosis factor (TNF) but enhanced the expression of genes responsible for synthesizing the extracellular matrix and promoting proliferation. Despite reduced expression of total Lyn in single-isoform Lyn knockout BMDMs, expression of either LynA or LynB alone was sufficient to preserve a wild-type-like transcriptome at steady state and after treatment with the TLR7 agonist R848. However, LynAKO and LynBKO macrophages did have impaired TNF production in response to the TLR4 agonist lipopolysaccharide. Additionally, LynAKO and LynBKO macrophages were as hyperproliferative as LynKO cells. These data suggest that Lyn promotes macrophage activation in response to TLR signaling and restrains aberrant proliferation and matrix deposition in a dose-dependent rather than isoform-specific manner.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238742","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":"Dynamic nucleosome redistribution and increases in nucleosome sensitivity underpin THP-1 macrophage response to LPS.","authors":"Jane M Benoit, Brandon D Buck, Mahdi Khadem, Hank W Bass, Jonathan H Dennis","doi":"10.1093/jleuko/qiaf067","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf067","url":null,"abstract":"<p><p>Macrophages detect lipopolysaccharide (LPS) through toll-like receptor 4 (TLR-4) on the cell surface which initiates a signaling cascade, resulting in the recruitment of regulatory factors to chromatin and subsequent expression of chemokine and cytokine genes. Primary response genes, marked by poised promoters and enhancers, are rapidly expressed after LPS stimulation, and their gene products activate secondary response genes via paracrine and autocrine signaling pathways. While the signaling cascades following macrophage activation are well understood, the dynamics of nucleosome architecture in promoter regions during early and late LPS responses remain unclear. Here, we stimulated THP-1 derived macrophages with LPS and assessed nucleosome distribution and MNase sensitivity across promoters at 8 time points spanning primary and secondary responses. We found that while nucleosome distribution was static over most promoters, LPS stimulation resulted in transient remodeling of a subset of innate immune gene promoters. We also observed distinct MNase sensitivity alterations in 2 phases which aligned with early and late gene expression patterns. Notably, while most Pol II promoters showed altered chromatin sensitivity, only a subset exhibited transcriptional changes, suggesting that widespread alterations in nucleosome distribution and sensitivity occur at promoters with or without alterations in gene expression. These findings provide new temporal insights into the transient and long-term effects of immune stimulation on promoter architecture and offer a methodological framework for additional time-resolved studies of chromatin remodeling in other systems.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199520","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":"Transient alterations in nucleosome distribution and sensitivity to nuclease define the THP-1 monocyte-to-macrophage transition.","authors":"Jane M Benoit, Brandon D Buck, Mahdi Khadem, Hank W Bass, Jonathan H Dennis","doi":"10.1093/jleuko/qiaf062","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf062","url":null,"abstract":"<p><p>The monocyte-to-macrophage transition is marked by alterations to both the structure and function of the genome, including changes in histone posttranslational modifications, DNA methylation, 3D nuclear architecture, and expression of lineage specific genes. The nucleosome is the fundamental organizational unit of the eukaryotic genome and underpins both genome structure and function. However, nucleosome dynamics at promoters, which are essential for transcriptional regulation, are understudied in cellular differentiation. We conducted high-resolution chromatin structure profiling at promoters in the THP-1 cell line at 8 different time points spanning phorbol-12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation. We found that fewer than 10% of nucleosomes within promoters were redistributed during differentiation and only a subset of these were associated with immediate transcriptional alterations. Nucleosomes within the promoters of PMA-responsive genes were strongly positioned prior to differentiation and experienced minimal alterations during differentiation, thus implying the existence of a predifferentiation primed chromatin state. Additionally, we observed pronounced alterations in nucleosome sensitivity to MNase digestion within 1 h of PMA-induced differentiation and the emergence of a highly resistant phenotype in fully differentiated cells. We found that resistance is correlated with active chromatin marks, transcription factor binding, gene expression, and higher-order chromatin structure, demonstrating that it is a useful measure of both genome structure and function. Together, this suggests that, unlike more stable nucleosome distribution, transient sensitivity alterations may underpin new genomic functions in differentiating cells. Our results offer a framework for understanding how chromatin structural alterations potentiate cellular differentiation in a monocyte model and use methodology that is widely applicable to other systems.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199588","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":"Tissue damage, myocardial injury and recruitment of mature and banded neutrophils after high-intensity endurance exercise.","authors":"Bernard N Jukema, S van Voorbergen, Sylvan L J E Janssen, Thijs M H Eijsvogels, Alma Mingels, Wim Vroemen, Nienke Vrisekoop, Leo Koenderman","doi":"10.1093/jleuko/qiaf137","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf137","url":null,"abstract":"<p><p>Neutrophils are key players in inflammatory responses that are modulated by cytokines/chemokines and damage associated molecular patterns (DAMPs). Exercise induces acute neutrophilia, but little is known regarding recruitment of neutrophil subsets (banded (CD16dim/CD62Lbright) and hypersegmented (CD16bright/CD62Ldim) cells) and it's relation with the liberation of markers of tissue damage. The aim was to investigate the neutrophil compartment in response to a single bout of high-intensity endurance exercise and the association with tissue damage, cortisol and myocardial injury. Blood samples were prospectively collected from 35 athletes participating in a long-distance trail-run (before, directly after, and 24 hours after exercise) for biomedical analysis. The neutrophil compartment was directly analyzed in the field by automated, mobile, flow cytometry. Linear regression analyses were performed for neutrophil (subset) counts versus tissue damage (CK, LDH and AST), cortisol and markers of cardiac injury. Neutrophilia was present directly after exercise, with the appearance of banded and hypersegmented neutrophils. This was accompanied by increased levels of markers of tissue damage, cortisol and cardiac troponins. Increased cortisol levels showed a positive correlation with the increase in cell counts of both banded and mature neutrophils. This correlation was not found for hypersegmented neutrophils. No relations were found between the neutrophil (subsets) and markers of tissue damage or cardiac troponins. This study demonstrates the recruitment of three distinct neutrophil subsets following a single bout of high-intensity endurance exercise. These results indicate an association between neutrophil recruitment after exercise and cortisol levels, rather than with tissue damage or cardiac injury.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199481","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":"Metformin improves CD8+ T cell responses and parasitemia control via macrophage modulation during Trypanosoma cruzi infection.","authors":"Ruth Eliana Baigorri, María Belén Brugo, Florencia Hellriegel, María Estefanía Viano, Yanina Luciana Mazzocco, Yamile Ana, Camila Fontanari, Matías Vazquez-Vignale, Maria Pilar Aoki, María Cecilia Rodriguez-Galán, Claudia Cristina Motrán, Cinthia Carolina Stempin, Fabio Marcelo Cerbán","doi":"10.1093/jleuko/qiaf134","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf134","url":null,"abstract":"<p><p>The immune response to Trypanosoma cruzi infection relies on robust inflammatory activation of macrophages and proper CD8+ T cells function to control parasite replication. However, an exacerbated respiratory burst from macrophages can damage tissues where parasites reside, such as the heart and liver. Subsequent fibrotic repair in the heart contributes to cardiomyopathy in patients with chronic Chagas disease and in mouse models. Additionally, respiratory burst metabolites are implicated in the impairment of CD8+ T cell responses. While excessive reactive oxygen species (ROS) production is associated with increased differentiation of Foxp3+ regulatory T cells (Tregs), T cell receptor (TCR) nitration occurs in the presence of high extracellular nitric oxide (NO) levels. Both mechanisms contribute to CD8+ T cell suppression during T. cruzi infection. In this study, we use metformin (Metf) to balance parasite control and immune-mediated tissue damage by modulating macrophage activation. We found that Metf ex vivo treatment in peritoneal macrophages (PEMs) from acutely infected mice led to reduced iNOS expression, decreased NO production and lower secretion of IL-1β, TNF and IL-6. However, IL-12 levels increased and CD8+ T cells co-cultured with these PEMs showed enhanced proliferation and IFN-γ production. In vivo, Metf-treated infected mice exhibited lower parasitemia and improved CD8+ T cell functionality, potentially linked to reduced TCR nitration and decreased Treg frequencies in the peritoneum, as well as reduced cardiac inflammation. These findings provide new insights into the inflammatory modulation exerted by Metf and its potential impact on CD8+ T cell response and Chagas disease outcome.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149428","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":"Resolved versus uncontrolled inflammation: a mathematical model to decipher the role of innate immunity.","authors":"Karina García-Martínez, Nuris Ledón, Agustín Lage","doi":"10.1093/jleuko/qiaf132","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf132","url":null,"abstract":"<p><p>Understanding the impact of Neutrophils and Macrophages in the dynamic outcome of resolution vs uncontrolled response is still an open debate. Here, we develop a mathematical model that describe the dynamic of the innate immune response after an acute damage. Our model includes all the described processes that mediate this response, including the regulatory mechanisms carried out by type-2 Macrophages (M2). Additionally, we estimate the resolution indices to quantify the efficiency of resolution mechanisms by controlling the initial expansion of Neutrophils and/or the subsequent contraction kinetics of the cell response. We predict that the partial reduction of Neutrophil influx and the increase of type-1 Macrophage (M1)-mediated efferocytosis rate are the best strategies to control the Neutrophil initial expansion. On the other hand, the partial reduction of M1 cells influx or the increase of Neutrophil apoptosis rate are predicted as good strategies to accelerate the Neutrophils decay during the contraction phase of the response.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149419","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":"GATA2 Induces a Stem Cell-Like Transcriptional Program in Macrophages That Promotes an Atherogenic Phenotype.","authors":"Amena Aktar, Angela M Vrieze, Kiera Telesnicki, Paisley Cox-Duvall, Matthew Arbolino, Rodney P DeKoter, A Dave Nagpal, Bryan Heit","doi":"10.1093/jleuko/qiaf136","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf136","url":null,"abstract":"<p><p>Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden necrotic macrophages within blood vessels walls. GATA2 is a normally hematopoietic transcription factor which in the bone marrow helps maintain the proliferative, non-differentiated phenotype of hematopoietic progenitors. Unexpectedly, GATA2 is upregulated in macrophages within atherosclerotic plaque, where it plays an unknown role in disease progression. Although GATA2 can be expressed from two promoters, we determined that the atherogenic stimuli oxidized low-density lipoprotein and TNFα induce GATA2 expression via the internal (IG) GATA2 promoter, with GATA2 transcription initiated by the transcription factors NF-κB, STAT1, and the aryl hydrocarbon receptor. GATA2 had a divergent effect on promoter activity, with GATA2 upregulating genes associated with stem cell maintenance, hematopoiesis, proliferation, reactive oxygen species production, and migration-while downregulating genes central to macrophage function including those for cholesterol efflux, pathogen phagocytosis, and for the efferocytosis of apoptotic cells. Consequentially, GATA2-expressing macrophages had a pro-atherogenic phenotype typified by highly motile cells exhibiting poor cholesterol efflux and impaired phagocytosis and efferocytosis. These results indicate that GATA2 upregulation induces an immature, stem cell-like phenotype in atheroma macrophages, that may promote plaque cellularity while compromising atheroprotective mechanisms such as cholesterol clearance and apoptotic cell removal.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149394","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":"Low density granulocytes in the pathogenesis of inflammatory disease.","authors":"Abigail S Nutley, Noelle Pisacano, Maria Prendecki","doi":"10.1093/jleuko/qiaf133","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf133","url":null,"abstract":"<p><p>Low density granulocytes (LDG) are a population of predominantly neutrophils that sit within the peripheral blood mononuclear cell layer following density centrifugation. Their presence in various inflammatory conditions raises the question of their role in disease pathogenesis. LDG may be a heterogeneous population identified to contain cells with variously activated, mature and immature phenotypes depending on the context. There is a lack of specific marker for these cells, leading to variation in how their surface phenotype is characterised. Differences in the phenotype of LDG from healthy individuals and during pregnancy compared to those seen in the disease state suggest that distinct subsets of LDG emerge during inflammatory disease. Subsets of LDG may contribute to the pathogenesis of disease through their proinflammatory functions, longevity in peripheral blood and retention within microvascular tissue, leading to damage of endothelial cells. LDG may also enhance the adaptive immune response through their interactions with T cells. Further research to define LDG surface phenotype and the expression and functions of distinct subsets in inflammatory diseases may identify these cells as potential therapeutic targets.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149377","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}