Journal of Leukocyte Biology最新文献

{"title":"CD300ld promotes neutrophil bacterial phagocytosis in sepsis.","authors":"Yuichi Akama, Atsushi Murao, Monowar Aziz, Ping Wang","doi":"10.1093/jleuko/qiaf063","DOIUrl":"10.1093/jleuko/qiaf063","url":null,"abstract":"<p><p>Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. Neutrophils act as first line of defense against infection, but their function can become impaired in sepsis. CD300 antigen-like family member d (CD300ld), predominantly expressed on neutrophils, associates with Fc receptor common gamma-chain (FcRγ chain), a component vital for phagocytosis. In this study, we investigated the role of CD300ld in neutrophil phagocytosis. Our results demonstrate a marked decrease in CD300ld expression on neutrophils isolated from both septic mice and patients. CD300ld was positively correlated with bacterial phagocytosis in neutrophils. The transcriptomic analysis of CD300ld knock-out neutrophils revealed a downregulation of genes related to defense response to bacteria, suggesting that CD300ld is a key modulator of bacterial clearance. Stimulation of CD300ld with an agonist antibody in neutrophils led to the activation of Rac2, a key regulator of actin polymerization, facilitating the enhanced phagocytosis. Furthermore, CD300ld activation significantly enhanced the in vitro phagocytosis of Escherichia coli and Staphylococcus aureus by neutrophils. Septic mice adoptively transferred with CD300ld-activated neutrophils exhibited markedly reduced bacterial loads in the blood and peritoneum, decreased inflammatory cytokine levels, and alleviated organ injury. These findings highlight the critical role of CD300ld signaling in neutrophil-mediated bacterial clearance in sepsis and provide a solid foundation for future research aimed at developing novel immunotherapies against this deadly disease condition.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078568","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":"Ferroptosis in neutrophils.","authors":"Yu-Bin Lee, Hyeong-Wook Shin, Sanjeeb Shrestha, Jun-Kyu Kim, Soo-Jung Jung, Min-Sang Shin, Chang-Won Hong","doi":"10.1093/jleuko/qiaf039","DOIUrl":"10.1093/jleuko/qiaf039","url":null,"abstract":"<p><p>Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation. The ferroptosis mechanism involves complex interactions between fatty acid metabolism, iron metabolism, lipid peroxidation, and antioxidative defense mechanisms. Fatty acids, especially polyunsaturated fatty acids, are susceptible to peroxidation, leading to the formation of lipid peroxides. Iron metabolism plays a critical role, as excessive free iron catalyzes the production of reactive oxygen species via the Fenton reaction, further promoting lipid peroxidation. Antioxidative mechanisms, including glutathione peroxidase 4 and other components of the glutathione system, are crucial for neutralizing lipid peroxides and preventing ferroptosis. Recent studies have highlighted the role of ferroptosis in neutrophils, particularly under pathological conditions. Neutrophils, due to their high iron content and abundance of polyunsaturated fatty acids, are inherently predisposed to ferroptosis. Recent studies indicate that polymorphonuclear myeloid-derived suppressor cells and tumor-infiltrating neutrophils exhibit high susceptibility to ferroptosis due to a dysregulated antioxidant defense mechanism through hypoxia-mediated downregulation of glutathione peroxidase 4. Conversely, tumor-infiltrating neutrophils resist ferroptosis through nuclear factor erythroid 2-related factor 2-dependent antioxidant pathway. Moreover, neutrophils induce ferroptosis in various cell types, such as endothelial cells, smooth muscle cells, and cardiomyocytes, through the release of neutrophil extracellular traps. This neutrophil extracellular trap-mediated ferroptosis contributes to the pathogenesis of conditions such as intestinal ischemia-reperfusion injury, aortic aneurysm, acute lung injury, and doxorubicin-induced cardiotoxicity. This review consolidates current knowledge on the mechanisms of ferroptosis in neutrophils and its implications in disease progression and immune regulation. Understanding these processes may provide new therapeutic targets for modulating immune responses and improving outcomes in ferroptosis-related diseases.</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":"143788517","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 complex immune exchange between mother and child continues to reveal surprising intricacies.","authors":"Licia Torres, Juan Miranda Peixoto, Tatiani Uceli Maioli","doi":"10.1093/jleuko/qiaf041","DOIUrl":"10.1093/jleuko/qiaf041","url":null,"abstract":"","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":"144015377","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":"UDP-glucose regulates dendritic cell mitochondrial respiration via a nitric oxide-dependent mechanism.","authors":"Bay Vagher, Soyeon K Gullickson, Julia P Snyder, Tyler Hogan, Roxana Del Rio-Guerra, Keke C Fairfax, Eyal Amiel","doi":"10.1093/jleuko/qiaf047","DOIUrl":"10.1093/jleuko/qiaf047","url":null,"abstract":"<p><p>Bone marrow-derived dendritic cell (BMDC) activation is associated with rewiring of cellular metabolism and concurrent large-scale changes in gene expression promoting a proinflammatory program characterized by expression of inducible nitric oxide synthase and the production of nitric oxide (NO). NO inhibits vital cellular activities including mitochondrial respiration. Mitochondrial respiration inhibition via NO occurs at discrete levels of activating stimulus, termed the mitochondrial respiration threshold, and regulation of this threshold is not fully understood. In this work, we characterize the role of uridine diphosphate glucose as a modulator of NO-mediated mitochondrial respiration inhibition via P2Y14 receptor signaling in stimulated BMDCs. We demonstrate that BMDCs exhibit an enhanced proinflammatory profile in the presence of uridine diphosphate glucose, providing evidence for a new NO regulatory axis in BMDCs. These studies highlight the importance of the growing body of literature supporting metabolites as signaling molecules in activating conditions thus allowing for better modeling of physiologically relevant contexts for myeloid cell encounters with microbial stimuli.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12089799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024456","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":"Distinct roles of PGE2 signaling via EP2 and EP4 in circulating pDCs: Implications for immune modulation in the tumor microenvironment.","authors":"Jorge Cuenca-Escalona, Mark W D Sweep, Mark A J Gorris, Tjitske Duiveman-de Boer, Alessandra Cambi, Georgina Flórez-Grau, Jolanda M de Vries","doi":"10.1093/jleuko/qiaf034","DOIUrl":"10.1093/jleuko/qiaf034","url":null,"abstract":"<p><p>Dendritic cells (DCs) play a pivotal role in orchestrating adaptive immunity in response to environmental cues such as prostaglandin E2 (PGE2). Tumors are known to establish a microenvironment rich in PGE2. Tumor-derived PGE2 is regarded as mediator of regulatory features in DCs, facilitating immune evasion and tumor progression. In DCs, the effects of PGE2 are mediated through the E-prostanoid receptor type 2 (EP2) and EP4. While the immunomodulatory effects of PGE2 signaling via EP2/4 in monocyte-derived DCs (moDCs) is well established, its role in human blood plasmacytoid DCs (pDCs) is poorly characterized. Therefore, in this study we investigated the effect of EP2 and EP4 signaling on pDC function, as well as the relevance of modulating these receptors in pDCs exposed to tumor-derived PGE2. Our findings reveal that EP2 and EP4 exhibit distinct functions in pDCs. PGE2-EP4 signaling mediates the upregulation of maturation markers (e.g., CD83 and HLA-DR), enhances a CCR7-based migratory function, impairs the production of proinflammatory mediators (e.g., interferon α and CXCL9), and stimulates the expansion of CD8 T cells with a marked suppressive phenotype. In contrast, PGE2-EP2 signaling hinders the upregulation of maturation markers and induces the expansion of CD8 T cells with a suppressive character. Additionally, using different in vitro tumor models, we show that EP2/4 blockade modulates the phenotype of pDCs exposed to tumor-derived PGE2. Together, these results identify the distinctive role of EP2 and EP4 signaling in pDCs and illustrate the potential therapeutic benefit of targeting this signaling axis to mitigate tumor-induced pDCs dysfunction.</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":"143670012","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":"Secretory IgA binding to FCRL3 triggers shared inflammatory cytokine secretion by human regulatory T cells and effector T cells.","authors":"Zachary Kraus, Shama Birla, Taylor Powell, Svetlana Petrovskaya, Frederick Mills, Jessica Dement-Brown, Casey Culhane, Kimia Dokhaee, Mate Tolnay","doi":"10.1093/jleuko/qiaf054","DOIUrl":"10.1093/jleuko/qiaf054","url":null,"abstract":"<p><p>Several human lymphocyte subsets express the novel secretory IgA receptor FCRL3 (Fc receptor-like 3). Secretory IgA binding to FCRL3 diminishes the inhibitory capacity of regulatory T cells and promotes a T helper 17-like phenotype. Here, we report that in CD4+ regulatory T cells and CD8+ terminal effector T cells secretory IgA induced a shared inflammatory gene signature that included PTGS2 encoding COX2, and the prototypic inflammatory cytokine genes IL1A, IL1B, and IL8. Secretory IgA in regulatory T cells also elevated gene transcripts required for lineage identity and function. Secretory IgA promoted interleukin (IL)-1β, IL-6, IL-8, IL-10, interferon γ, and tumor necrosis factor α protein secretion by both T cell types. Moreover, secretory IgA promoted NLRP3 inflammasome activation in regulatory T cells. Pharmacologic COX2 and NLRP3 inhibitors partially rescued the inhibitory competence of regulatory T cells, suggesting respective mechanistic roles. We propose that secretory IgA provokes a coordinated inflammatory response in regulatory and effector T cells to facilitate mucosal pathogen clearance.</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":"144017167","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":"Temporal immune profiling in the cerebrospinal fluid and blood of patients with aneurysmal subarachnoid hemorrhage.","authors":"Thomas A Ujas, Katie L Anderson, Jenny Lutshumba, Samantha N Hart, Jadwiga Turchan-Cholewo, Kevin W Hatton, Adam D Bachstetter, Barbara S Nikolajczyk, Ann M Stowe","doi":"10.1093/jleuko/qiaf038","DOIUrl":"10.1093/jleuko/qiaf038","url":null,"abstract":"<p><p>Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset. Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. PB mononuclear cells (PBMCs) were collected, and their cytokine production quantified following stimulation. Mixed-effects models reveal distinct immune cell dynamics in CSF compared with blood. Monocyte/macrophage numbers continue to increase in both CSF and PBMCs for days post-aSAH. CD4+ human leukocyte antigen II+ T cells and CD8+ CD154+ T cells increased in circulation over time. Unstimulated PBMCs showed increased interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha production, peaking at 7 d post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 d postinjury, preceding immune cell profile alterations. Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a potential therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12104984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742988","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":"Afucosylated broadly neutralizing antibodies targeting the HIV envelope elicit enhanced NK-cell-mediated cytotoxicity against HIV-infected CD4+ T-cell and macrophage targets.","authors":"Olivia Wilhelm, Christine Jordan, Hans Kek, Morgane M Brunton-O'Sullivan, Laura Rikard-Bell, Pradhipa Ramanathan, Amy W Chung, Pantelis Poumbourios, Bruce D Wines, Anthony Jaworowski, Anna C Hearps","doi":"10.1093/jleuko/qiaf033","DOIUrl":"10.1093/jleuko/qiaf033","url":null,"abstract":"<p><p>Enhancement of antibody-dependent cellular cytotoxicity is a promising adjunct approach to achieve HIV control in the absence of antiretroviral therapy but requires the development of potent antibody-dependent cellular cytotoxicity-eliciting antibodies that can recognize diverse HIV-infected cell types. A panel of broadly neutralizing antibodies targeting the HIV envelope was identified that specifically binds both HIV-infected CD4+ T cells and monocyte-derived macrophages. Afucosylated versions of these broadly neutralizing antibodies containing ≈30% less core fucose were generated and elicited a significant increase in antibody-dependent cellular cytotoxicity responses from natural killer cells against HIV-infected T-cell and monocyte-derived macrophage targets. Afucosylation did not alter virus neutralization or cell-binding activity of these broadly neutralizing antibodies. Afucosylation modification of broadly neutralizing antibody Fc regions is thus a promising strategy to enhance Fc-mediated activity against both T-cell and macrophage targets in vivo, which may be employed to heighten the therapeutic potential of antibody-based immunotherapy approaches for drug-free HIV control.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630674","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":"Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia.","authors":"Devashis Mukherjee, Sriram Satyavolu, Asha Thomas, Sarah Cioffi, Yuexin Li, E Ricky Chan, Katherine Wen, Alex Y Huang, Mukesh K Jain, George R Dubyak, Lalitha Nayak","doi":"10.1093/jleuko/qiaf040","DOIUrl":"10.1093/jleuko/qiaf040","url":null,"abstract":"<p><p>Preterm neonates die at a significantly higher rate from sepsis than full-term neonates, attributable to their dysregulated immune response. In addition to tissue destruction caused directly by bacterial invasion, an overwhelming cytokine response by the immune cells to bacterial antigens also results in collateral damage. Sepsis leads to decreased gene expression of a critical transcription factor, Krüppel-like factor-2 (KLF2), a tonic repressor of myeloid cell activation. Using a murine model of myeloid-Klf2 deletion, we show that loss of KLF2 is associated with decreased survival after endotoxemia in a developmentally dependent manner, with increased mortality at postnatal day 4 (P4) compared to P12 pups. This survival is significantly increased by neutrophil depletion. P4 knockout pups have increased proinflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1β, a product of the activation of the NLRP3 inflammasome complex. Loss of myeloid-KLF2 at an earlier postnatal age leads to a greater increase in NLRP3 priming and activation and greater IL-1β release by BMNs. Inhibition of NLRP3 inflammasome activation by MCC950 significantly increased survival after endotoxemia in P4 pups. Transcriptomic analysis of bone marrow neutrophils showed that loss of myeloid-KLF2 is associated with gene enrichment of proinflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the proinflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis.</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":"143764101","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":"Hematopoietic stem and progenitor cells fine-tuning the \"sweet\" of trained immunity.","authors":"Jiawei Li, Hui Wang, Sheng Xia","doi":"10.1093/jleuko/qiaf043","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf043","url":null,"abstract":"<p><p>Recent studies have challenged the traditional view of innate immunity as nonspecific and transient by demonstrating that innate immune cells can develop immune memory in response to various activating factors, a phenomenon known as trained immunity. This process involves epigenetic modifications, such as changes in chromatin accessibility, and metabolic reprogramming, which can provide protection against unrelated pathogens but may also trigger immune-mediated damage. This review summarizes the current understanding of innate immune memory, with a particular focus on recent findings regarding the training of innate immune cells at the hematopoietic stem and progenitor cell stage. We present observations of trained immunity in innate immune cells, summarize key activating factors and underlying mechanisms, and propose potential host-directed immunotherapeutic strategies and preventive measures based on trained immunity. Our aim is to highlight the biological significance of trained immunity and its potential applications in enhancing long-term immunity, improving vaccine efficacy, and preventing immune-related diseases.</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":"143995587","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}