Journal of Leukocyte Biology最新文献

{"title":"Neutrophil CD300ld: a savior of organ failure?","authors":"Duane Jeansonne, Samithamby Jeyaseelan","doi":"10.1093/jleuko/qiaf101","DOIUrl":"10.1093/jleuko/qiaf101","url":null,"abstract":"","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560385","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":"A comprehensive phenome wide analysis of the role of neutrophils in health and disease.","authors":"Katy Fleming, Naomi Cornish, Emma E Vincent, Andrew D Mumford, Borko Amulic, Kate Burley","doi":"10.1093/jleuko/qiaf076","DOIUrl":"10.1093/jleuko/qiaf076","url":null,"abstract":"<p><p>Neutrophil release of cytoplasmic granules containing antimicrobial agents is a critical component of innate immunity. Neutrophils are widely implicated in tissue inflammation however the extent of the neutrophil contribution to human health and disease is incompletely characterized. To explore this further, we leveraged publicly available genetic data to conduct a Mendelian randomization phenome-wide association study (MR-PheWAS) of neutrophil traits and 14,983 outcomes. Genetic proxies for neutrophil count, granularity, and serum myeloperoxidase were linked to 145 outcomes. Higher neutrophil count was associated with lower body weight, reduced obesity risk, and increased vascular activation markers but not with atherosclerosis. Elevated neutrophil count was robustly linked to Alzheimer's disease and neutrophil granularity with gut microbiota abundance and dental pathology. Our findings reveal the diverse roles of neutrophils extending beyond pathogen defense and underscore the potential for MR-PheWAS in identifying novel neutrophil-related pathophysiology.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174347","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":"Macrophage IL-4 polarization is restricted by soluble CD40 agonists and antigen-induced CD154 but not by constitutive CD154 expressed by CD4+ T cells.","authors":"Mariana Suárez-Martins, Ignacio González-Alayón, Cecilia Casaravilla, Louis Boon, Pedro H Papotto, Conor M Finlay, Stephen J Jenkins, Judith E Allen, Álvaro Díaz","doi":"10.1093/jleuko/qiaf069","DOIUrl":"10.1093/jleuko/qiaf069","url":null,"abstract":"<p><p>Stimulation of macrophages via CD40 promotes their classical activation. Therefore, CD154 (CD40 ligand) can be expected to oppose macrophage polarization and proliferation induced by IL-4. However, there are limited experimental data to support this, which is additionally complicated by the possibility of differential effects of CD40 agonists in different formats/contexts. Whereas canonically CD4+ T cells upregulate CD154 strongly following exposure to cognate antigen, naïve CD4+ cells constitutively express significant levels of CD154, which could be a tonic signal. Soluble CD154 and agonistic CD40 antibodies also trigger CD40 signaling. We explored these questions in a reductionist model of IL-4 delivery to mouse peritoneal cavity cells in vitro and in vivo. Soluble CD40 agonists inhibited M(IL-4) polarization, with a stronger effect on RELM-α than on Ym1 (Chil3), as well as inhibiting IL-4-induced proliferation. CD154 provided by CD4+ cells in the context of an antigen-specific interaction blunted macrophage RELM-α expression but did not affect Ym1. Macrophages negatively regulated, via CD40, constitutive cell-surface CD154 on naïve CD4+ cells, both in vitro and in vivo. The large peritoneal macrophages of CD40 KO mice showed a moderately enhanced RELM-α response to IL-4, but this was not a cell-autonomous effect. No differences between WT and CD40 KO mice were detected in IL-4-induced macrophage proliferation. We conclude that strong CD40 stimulation, including stimulation by CD154 expressed by antigen-specific CD4+ cells, blunts selected macrophage responses to IL-4, and that constitutive CD4+-cell CD154, in spite of interacting with CD40 on macrophages, does not directly influence macrophage responses to IL-4.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 7","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591402","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":"Sex-specific leukocyte responses to peanut allergen: uncovering potential links to the molecular circadian clock.","authors":"Santhosh Kumar Duraisamy, Isaac Kirubakaran Sundar","doi":"10.1093/jleuko/qiaf097","DOIUrl":"10.1093/jleuko/qiaf097","url":null,"abstract":"<p><p>Food allergies, particularly peanut allergies, are on the rise, affecting ∼10% of the U.S. population and 17% of adults. We explored sex-based differences in inflammatory responses to peanut allergens using a mouse model. Female mice exhibited severe allergic symptoms and a greater drop in body temperature than males when challenged with peanut extract and cholera toxin. Females showed higher levels of interstitial macrophages and neutrophils, while males showed increased eosinophil and lymphocyte influx. Elevated cytokines (IL-4, IL-5, and IL-9) in females correlate with increased IgE and histamine, indicating heightened mast cell activation. Reduced expression of the circadian gene Rev-erbα in female intestines post-challenge suggests a link between inflammatory responses and circadian disruption. IgE/mast cell and IgG/neutrophil-mediated pathways appeared to be involved in female responses. These findings suggest that hormonal and circadian influences may play critical roles in sex-based differences in peanut allergen, with further investigation needed to elucidate the underlying mechanisms.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505984","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":"Fibroblast activation protein on human natural killer cells: insights from natural killer cell activation and crosstalk with cancer-associated fibroblasts.","authors":"Yentl Van Rymenant, Anke de Groot, Laura Dirkx, Emile Verhulst, Joni De Loose, Isabel Pintelon, Tias Verhezen, Jorrit De Waele, Sofie Thys, Olivier De Wever, Muhammet Tanc, Guy Caljon, Pieter Van der Veken, Ingrid De Meester","doi":"10.1093/jleuko/qiaf103","DOIUrl":"10.1093/jleuko/qiaf103","url":null,"abstract":"<p><p>Fibroblast activation protein alpha is a postprolyl proteolytic enzyme highly expressed in the tumor microenvironment, particularly in cancer-associated fibroblasts. Although previously thought to be restricted to cancer-associated fibroblasts, malignant cells, and pathological fibroblasts, recent studies have identified fibroblast activation protein expression in natural killer cells. However, its expression and activity in natural killer cells remain poorly characterized. Here, we investigated fibroblast activation protein expression and activity in resting and cytokine-stimulated (interleukin-2 and interleukin-15) primary human natural killer cells and NK92 cells. Natural killer cell activation resulted in a significant decrease in fibroblast activation protein expression and enzymatic activity. Treatment with the fibroblast activation protein inhibitor UAMC-1110 altered the expression of activating and inhibitory natural killer cell receptors and reduced perforin expression, though it did not impact degranulation or cytotoxic function. Culturing natural killer cells in cancer-associated fibroblast-conditioned medium or direct co-culture with cancer-associated fibroblasts increased fibroblast activation protein expression and activity in NK92 cells, with donor-dependent effects observed in primary natural killer cells. These conditions also led to a reduction in natural killer activating and inhibitory receptor expression. Furthermore, hypoxia upregulated fibroblast activation protein in both NK92 and primary natural killer cells. Overall, our findings demonstrate that fibroblast activation protein is downregulated in/on natural killer cells upon activation with interleukin-2 and interleukin-15, whereas it is upregulated under tumor microenvironment-mimicking conditions. This may suggest that fibroblast activation protein contributes to the phenotype formation of natural killer cells, particularly within the tumor microenvironment, where we hypothesize that natural killer cells might prioritize invasive capacity over cytotoxic capacity, thus upregulating fibroblast activation protein.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608582","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":"Pre-ligand assembly domain-derived recombinant protein of TNFR2 inhibits the expansion of CD4+ Foxp3+ regulatory T cells.","authors":"Wen-Wei Li, Chuangen Li, Yang Yang, Yibo Chen, Zhonghao Chen, Yang Gao, Yiru Wang, Tao Liu, Xin Chen, Chon-Kit Chou","doi":"10.1093/jleuko/qiaf087","DOIUrl":"10.1093/jleuko/qiaf087","url":null,"abstract":"<p><p>There is compelling evidence that tumor necrosis factor (TNF) receptor type II (TNFR2) mediates the stimulatory effect of TNF on the activation of CD4+ Foxp3+ regulatory T cells (Tregs). Tregs with high TNFR2 expression are critical components of tumor microenvironment, where they promote tumor progression by impeding antitumor immune responses. Thus, selectively targeting TNFR2 has emerged as a promising strategy to inhibit Treg activity and enhance antitumor immune responses. The preligand-binding assembly domain (PLAD) is a conserved extracellular domain that subtly differs among TNF receptor family members, facilitating the ligand-independent assembly of receptor monomers into a spatially optimal trimer that favors ligand binding. Previous studies demonstrated that recombinant PLAD proteins derived from TNFR1 were able to inhibit TNFR1-mediated cell death and alleviated inflammatory conditions in mouse models. However, the functional properties of TNFR2-derived PLAD remain largely unexplored. In this study, we developed recombinant PLAD proteins from human and mouse TNFR2, as well as TNFR1, and evaluated their ability to interfere with TNF binding and Treg activation. All 4 PLAD proteins dose-dependently inhibited TNF-stimulated NF-κB transcriptional activity in HEK293 reporter cells. Among them, human TNFR2-derived PLAD exhibited relatively enhanced inhibitory effects compared with the other 3 in HEK293 reporter cells overexpressing TNFR2 but lacking TNFR1, and potently blocked TNF binding to TNFR2 on Jurkat cell surfaces. Furthermore, human TNFR2-derived PLAD significantly reduced the TNF-induced proliferative expansion of CD4+ Foxp3+ Tregs in both mouse lymphocyte and human peripheral blood mononuclear cell cultures. Our findings suggest that human TNFR2-derived PLAD merits further investigation for the cancer immunotherapy.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505983","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":"Arginine metabolism supports metabolic reprogramming in trained immunity.","authors":"Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea","doi":"10.1093/jleuko/qiaf080","DOIUrl":"10.1093/jleuko/qiaf080","url":null,"abstract":"<p><p>Trained immunity, also termed innate immune memory, is supported by the metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells' phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated the induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216083","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":"Ageing affects the CD4+ T cell polarization and mucosal tropism induced by TLR2/TLR4-activated dendritic cells.","authors":"Sara Zúquete, Mariana Ferreira, Inês L S Delgado, Maria Teresa Rosa, Ana Catarina Mendes, Dulce Santos, Sofia Nolasco, Luis Graca, Alexandre Leitão, Afonso P Basto","doi":"10.1093/jleuko/qiaf096","DOIUrl":"10.1093/jleuko/qiaf096","url":null,"abstract":"<p><p>Toll-like receptor (TLR)2 activation induces aldehyde dehydrogenase enzymes in nonmucosal dendritic cells (DCs) enabling them to metabolize vitamin A into all-trans retinoic acid, which induces the expression of mucosal homing molecules (α4β7 and CCR9) in the activated T cells. Recently, we have shown that the simultaneous activation of nonmucosal DCs through TLR2 and TLR4 maintains such capacity while reinforcing the polarization of primed CD4+ T cells towards Th1. Here, we observed that TLR2/TLR4 stimulation of aged DCs leads to the production of less TNFα and more IL-10 and that CD4+ T cells primed by those DCs express lower levels of the mucosal homing receptor CCR9 and produce less type-1 (IFNγ) and more type-2 (IL-4 and IL-13) cytokines. These results emphasize the importance of considering the age-related alterations in DC function when developing novel immunomodulation strategies that rely on the DC-T cell crosstalk through stimulation of pattern recognition receptors.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505981","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":"Complexity of the neutrophil transcriptome in early and severe rheumatoid arthritis. A role for microRNAs?","authors":"Michele Fresneda Alarcon, Genna Ali Abdullah, John Alexander Beggs, Isobel Kynoch, Andrew Sellin, Andrew Cross, Sam Haldenby, Philipp Antczak, Eva Caamaño Gutiérrez, Helen Louise Wright","doi":"10.1093/jleuko/qiaf090","DOIUrl":"10.1093/jleuko/qiaf090","url":null,"abstract":"<p><p>Neutrophils are innate immune cells that drive the progression of rheumatoid arthritis (RA) through the release of reactive oxygen species (ROS), neutrophil extracellular traps (NETs) and proteases that damage host tissues. Neutrophil activation is regulated, in part, by dynamic changes in gene expression. In this study we have used RNAseq to measure the transcriptomes of neutrophils from people with severe, methotrexate-refractory RA and healthy controls. We identified a dynamic gene expression profile in people with severe RA. This is dominated by a type-I interferon-induced gene expression signature as well as activation of genes regulating neutrophil degranulation, NET production, response to ROS and oxidative stress. Whilst we did not detect significantly elevated levels of interferon-alpha in RA blood sera, we identified increased expression in RA neutrophils of miR-96-5p and miR-183-5p which regulate activation of the interferon pathway as members of the miR-183C cluster. We also detected significantly elevated NET debris in RA blood sera (p<0.05). Using gene set variation analysis we explored the heterogeneity of neutrophil gene expression in RA and identified subsets of patients with gene expression profiles reflecting enhanced neutrophil degranulation and cytotoxicity, tissue inflammation or activation by interferons. Comparison with published single-cell RNAseq datasets identified RA transcriptomes where neutrophils were polarised by genes relating to early or late cell maturity, with significant genes in each polarised state being regulated by miR-146a-5p, miR-155-5p, miR-183-5p or miR-96-5p. Overall our study demonstrates the heterogeneity of the RA neutrophil transcriptome and proposes miRNA-driven mechanisms for regulating the activated neutrophil phenotype in RA.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511991","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":"TIPE regulates TGFB2 expression and induces extracellular M2 polarization in CRC.","authors":"Qiang Zhu, Shiying Zhang, Changxiu Yan, Zeyang Lin, Shuaishuai Zhang, Haoyang Li, Yuhan Ye, Zhongchen Liu, Guohong Zhuang, Kun Zhang","doi":"10.1093/jleuko/qiaf066","DOIUrl":"10.1093/jleuko/qiaf066","url":null,"abstract":"<p><p>The immunosuppressive tumor microenvironment (TME) is a critical determinant of therapeutic resistance in colorectal cancer (CRC). The TME encompasses diverse cellular and stromal elements, including tumor cells, immune cells, extracellular matrix, and lymphatic vessels. Among these components, tumor-associated macrophages predominate both quantitatively and functionally, with M2-polarized macrophages being the principal subset responsible for immunosuppression. Identifying genes that promote M2 polarization from CRC would provide a more targeted approach to addressing this issue at its root. In this study, we demonstrate that TIPE derived from CRC indirectly stimulates extracellular M2 polarization. Mechanistically, TIPE activates the P38 MAPK signaling pathway, leading to increased expression and secretion of TGFB2, which subsequently acts on extracellular macrophages to induce M2 polarization. Moreover, M2 macrophages polarized by CRC-derived factors exert a feedback loop that enhances CRC proliferation, migration, and invasion, with the effect intensifying as TIPE expression in CRC increases. Animal experiments have also revealed that TGFB2 induced by TIPE can disseminate systemically via the bloodstream, influencing not only peritumoral macrophages but also inducing M2 polarization in macrophages in distant organs. Collectively, our findings indicate that TIPE from CRC can indirectly polarize extracellular macrophages to an M2 phenotype, thereby amplifying the malignant behavior of CRC.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101954","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}