Journal of Leukocyte Biology最新文献

{"title":"The interaction of Galectin-8 C-terminal domain with cell surface glycoconjugates modulates membrane elasticity to stimulate antigen uptake and presentation to CD4 T cells.","authors":"Cecilia A Prato, Laura V Borbolla, Leonardo Lizarraga, Oscar Campetella, María V Tribulatti","doi":"10.1093/jleuko/qiae214","DOIUrl":"10.1093/jleuko/qiae214","url":null,"abstract":"<p><p>Galectins constitute a family of soluble lectins with unique capacity to induce macroscale rearrangements upon interacting with cell membrane glycoconjugates. Galectin-8 is acknowledged for its role in facilitating antigen uptake and processing upon engaging with cell surface glycoconjugates on antigen-presenting cells. Galectin-8 consists of two covalently fused N- and C-terminal carbohydrate recognition domains, each exhibiting distinct glycan specificity. In this study, we utilized single N- and C-carbohydrate recognition domains recombinant proteins to dissect the nature of Galectin-8-glycan interactions during antigen internalization enhancement. Single C-carbohydrate recognition domain was able to replicate the effect of full-length Galectin-8 on antigen internalization in bone marrow-derived dendritic cells. Antigen uptake enhancement was diminished in the presence of lactose or when N-glycosylation-deficient macrophages served as antigen-presenting cells, underscoring the significance of glycan recognition. Measurement of the elastic modulus using Atomic Force Microscopy unveiled that full-length Galectin-8- and C-carbohydrate recognition domain-stimulated macrophages exhibited heightened membrane stiffness compared to untreated cells, providing a plausible mechanism for their involvement in endocytosis. C-carbohydrate recognition domain proved to be as efficient as full-length Galectin-8 in promoting antigen degradation, suggesting its implication in antigen-processing induction. Lastly, C-carbohydrate recognition domain was able to replicate full-length Galectin-8-induced antigen presentation in the major histocompatibility complex class II (MHC-II) context both in vitro and in vivo. Our findings support the notion that Galectin-8 binds through its C-carbohydrate recognition domain to cell surface N-glycans, thereby altering membrane mechanical forces conducive to soluble antigen endocytosis, processing, and presentation to cognate CD4 T cells. These findings contribute to a deeper comprehension of Galectin-8 and its mechanisms of action, paving the way for the development of more efficacious immunotherapies.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372059","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":"Blood immune profiles reveal a CXCR3/CCR5 axis of dysregulation in early sepsis.","authors":"David J Kealy, Julie C Wilson, Tom Jaconelli, Karen Hogg, Rebecca Coop, Greg Forshaw, Neil Todd, David Yates, Nathalie Signoret","doi":"10.1093/jleuko/qiae204","DOIUrl":"10.1093/jleuko/qiae204","url":null,"abstract":"<p><p>We report on a pilot study exploring whether blood immune signatures can reveal early specific indicator profiles for patients meeting sepsis criteria upon hospital admission. We analyzed samples of sepsis-suspected patients (n = 20) and age-spanning healthy controls (n = 12) using flow cytometry-based assays. We measured inflammatory markers from plasma fractions and immunophenotyped freshly isolated unfixed peripheral blood mononucleated cells for leukocyte subset representation and expression of activation markers, including chemokine receptors. We found that besides IL-6 and sCD14, CXCR3 ligands (CXCL9 and CXCL10) separated sepsis-suspected patients from healthy controls. The abundance of CD4+ T cells was significantly reduced in patients, while they displayed substantial losses of CCR5-expressing monocytes and CXCR3/CCR5 double-positive T cells. Post hoc subgrouping of patients according to their sepsis diagnosis on discharge identified CXCR3/CCR5 double expression on T cells as a separating characteristic for confirmed cases. This work suggests a potential novel axis of dysregulation affecting CXCR3 and CCR5 in early sepsis.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289240","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":"Limited proteolysis of neutrophil granule proteins by the bacterial protease RgpB depletes neutrophil antimicrobial capacity.","authors":"Kelley N Cooper, Aleksandra Wielento, Savannah C Morris, Marina Terekhova, Carlos J Rodriguez-Hernandez, Barbara Potempa, Katherine A Carey, Maxim N Artyomov, Jan Potempa, Juhi Bagaitkar","doi":"10.1093/jleuko/qiae209","DOIUrl":"10.1093/jleuko/qiae209","url":null,"abstract":"<p><p>Neutrophils are highly abundant in the gingival tissues where they play an essential role in immune homeostasis by preventing microbial invasion. Here, we show that the oral periodontal pathogen Porphyromonas gingivalis utilizes its cysteine proteases (gingipains) to disengage phagosomal antimicrobial capacity. Arginine gingipains are a subfamily of trypsin-like proteases produced by P. gingivalis that cleave several host proteins at arginine residues. We find that RgpB-mediated proteolysis of host proteins is not limited to the extracellular or plasma membrane-associated host proteins, but also results in the degradation of several intracellular proteins. Using 2D-difference gel electrophoresis coupled with mass spectrometry, we identified several cytoskeletal and cytoplasmic proteins, including metabolic enzymes and antimicrobial proteins such as neutrophil elastase, myeloperoxidase, and proteinase 3 within neutrophil granules that were cleaved by RgpB. Strikingly, despite the breakdown of multiple proteins, RgpB-treated neutrophils did not undergo apoptosis but increased integrin expression and underwent broad transcriptional changes consistent with proinflammatory programming. However, despite their primed status and augmented inflammatory capacity, RgpB-treated neutrophils were conducive to intracellular bacterial survival due to the reduced activity of granule proteins and oxidative burst. Thus, our data show a previously unknown role for P. gingivalis proteases in the attenuation of neutrophil microbicidal capacity via proteolysis of intracellular proteins.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348322","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":"B-cell interleukin 1 receptor 1 modulates the female adipose tissue immune microenvironment during aging.","authors":"Anna Carey, Louise E Pitcher, In Hwa Jang, Katie Nguyen, Stephanie Cholensky, Paul D Robbins, Christina D Camell","doi":"10.1093/jleuko/qiae219","DOIUrl":"10.1093/jleuko/qiae219","url":null,"abstract":"<p><p>Myeloid cell production of interleukin-1β (IL-1β) drives inflammaging in visceral white adipose tissue (vWAT) and contributes to the expansion of interleukin-1 receptor 1 (Il1r1)-positive aged adipose B cells (AABs). AABs promote metabolic dysfunction and inflammation under inflammatory challenges. However, whether IL-1β contributes to AAB-associated inflammation during aging is unclear. Using a B-cell-specific knockout of Il1r1 (BKO mice), we characterized old vWAT in the absence of IL-1β-B-cell signaling. In addition to sex-specific metabolic improvements in females, we identified a reduction in the proportion of B cells and a sex-specific increase in the B1/B2 B-cell ratio in BKO vWAT. Using single-cell RNA sequencing of vWAT immune cells, we observed that BKO differentially affected inflammatory signaling in vWAT immune cells. These data suggest that IL-1β-B-cell signaling supports the inflammatory response in multiple cell types and provides insight into the complex microenvironment in aged vWAT.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391086","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":"Unraveling immune heterogeneity across pan-cancer and deep insights in lung adenocarcinoma based on alternative splicing.","authors":"Yuquan Wang, Erliang Guo, Min Zou, Chen Lv, Yanrui Cui, Songmei Zhai, Shaocong Sang, Kai Xiong, Xiuqi Yang, Shuping Zhuang, Yunyan Gu, Haihai Liang","doi":"10.1093/jleuko/qiae104","DOIUrl":"10.1093/jleuko/qiae104","url":null,"abstract":"<p><p>Alternative splicing (AS) participates in tumor development and tumor microenvironment formation. However, the landscape of immune-infiltrating AS events in pan-cancer and mechanisms of AS in lung adenocarcinoma (LUAD) have not been comprehensively characterized. We systematically profiled the immune-infiltrating AS event landscape of pan-cancer using data from The Cancer Genome Atlas, analyzing both commonalities and specific characteristics among different cancer types. We found that AS events tend to occur specifically in one cancer type rather than in multiple cancer types. AS events were used to classify 512 LUAD samples into 2 subtypes by unsupervised clustering: the aberrant splicing subtype and the immune-infiltrating subtype. The 2 subtypes showed significant differences in clinicopathology, prognosis, transcriptomics, genomics, and immune microenvironment. We constructed a classification signature comprising 10 genes involved in 14 AS events using logistic regression. The robustness of the signature was validated in 3 independent datasets using survival analysis. To explore AS mechanisms in LUAD, we constructed subtype-specific coexpression networks using Pearson correlation analysis. AS event of AKT3 regulated by splicing factor ENOX1 was associated with poor prognosis in LUAD. Overall, we outline AS events associated with immune infiltration in pan-cancer, and this study provides insights into AS mechanisms in LUAD patient classification.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957676","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":"Immunoresponsive gene 1 facilitates TLR4 agonist-induced augmentation of innate antimicrobial immunity.","authors":"Margaret A McBride, Katherine R Caja, Tazeen K Patil, Allison M Owen, Liming Luan, Julia K Bohannon, Antonio Hernandez, Cody L Stothers, Irina A Trenary, Mohsin Rahim, Jamey D Young, M Wade Calcutt, Victoria R Stephens, Xenia Davis, Mary A Oliver, Dan Hao, Clara Si, Malik McRae, Kenny K Nguyen, Nicholas S Davis, Jingbin Wang, Naeem K Patil, Edward R Sherwood","doi":"10.1093/jleuko/qiae198","DOIUrl":"10.1093/jleuko/qiae198","url":null,"abstract":"<p><p>Treatment with the toll-like receptor 4 agonist monophosphoryl lipid A conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid cycle reprogramming to innate immune memory. We observed that priming of wild-type mice with monophosphoryl lipid A potently facilitated accumulation of the tricarboxylic acid cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in Irg1-deficient mice. We further observed that monophosphoryl lipid A potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to wild-type macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. Monophosphoryl lipid A-induced augmentation of glycolysis, oxidative phosphorylation, and accumulation of the tricarboxylic acid cycle metabolites succinate and malate was decreased in Irg1 knockout macrophages compared to wild-type controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1-deficient macrophages. This study identifies a contribution of itaconate to monophosphoryl lipid A-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348321","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":"Immunometabolic chaos in septic shock.","authors":"Deepmala Shrestha, Bishnu D Pant, Sanjoy Roychowdhury, Anugraha Gandhirajan, Emily Cross, Mamta Chhabria, Seth R Bauer, Margaret Jeng, Megan Mitchell, Omar Mehkri, Fatima Zaidi, Akash Ahuja, Xiaofeng Wang, Yuxin Wang, Christine McDonald, Michelle S Longworth, Thaddeus S Stappenbeck, George R Stark, Rachel G Scheraga, Vidula Vachharajani","doi":"10.1093/jleuko/qiae211","DOIUrl":"10.1093/jleuko/qiae211","url":null,"abstract":"<p><p>Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: (i) Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and (ii). Plasma metabolomic profile by Metabolon. Inc. (iii) We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: (i) The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. (ii) A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. (iii) In vitro exposure to 5 metabolites repressed while 2 metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348320","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":"Combination therapy with immune agonists and senescence-inducing agents delivers promise for immunotherapeutic success in pancreatic cancer.","authors":"Renee R Anderko, Amer H Zureikat, Tullia C Bruno","doi":"10.1093/jleuko/qiae234","DOIUrl":"10.1093/jleuko/qiae234","url":null,"abstract":"","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545881","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":"Risk beyond neutropenia: insights into neutrophil migration from newly diagnosed AML until late after allogeneic stem cell transplantation.","authors":"Zülal Cibir, Alexander Beer, Andreas Kraus, Aleksandra Pillibeit, Dana Bludau, Haji Abdulla, Nina Rosa Neuendorff, Justin Sonneck, Lennart Kowitz, Stefanie Riese, Ali Ata Tuz, Jianxu Chen, Maxim Cherneha, Dietrich W Beelen, H Christian Reinhardt, Matthias Gunzer, Amin T Turki","doi":"10.1093/jleuko/qiae250","DOIUrl":"https://doi.org/10.1093/jleuko/qiae250","url":null,"abstract":"<p><p>Quantification of neutrophil counts is the most relevant assessment of cellular immunity in clinical practice. Patients with neutropenia are considered at risk and are categorized according to its severity. The incidence of febrile neutropenia varies, but patients with acute myeloid leukemia are traditionally considered at high risk, especially following myelotoxic treatments. To provide additional functional parameters, we investigated the ex vivo migration properties and morphology of neutrophils in 10 patients with acute myeloid leukemia using single-cell video-microscopy and discovered, in addition to neutropenia, highly pathological neutrophil migration patterns and polarization defects in patients with untreated acute myeloid leukemia. Neutrophil speed was the most sensitive parameter and significantly lower at leukemia diagnosis (9.067 vs 15.810 µm/min, P = 0.0025) compared to healthy controls (n = 46). Hematological remission was associated with improved neutrophil migration profiles, but these ultimately normalized only after hematopoietic cell transplantation. Five patients were followed up for long-term effects of hematopoietic cell transplantation for up to 24 mo. This is the first longitudinal ex vivo neutrophil migration study in patients with acute myeloid leukemia, followed by allogeneic hematopoietic cell transplantation. It identified functional neutrophil impairments beyond routine quantitative assessments, adding to the well-known quantitative impairment of neutropenia. HCT can reestablish functional neutrophils with healthy migration profiles in these patients.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"117 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425598","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 129 strain-derived passenger mutations in ACKR1-deficient mice alter the expression of PYHIN and Fc-gamma receptor genes.","authors":"Zoe Möller-Ramon, Maria Aslani, Nikola Sobczak, Michael Hristov, Christian Weber, Antal Rot, Johan Duchêne","doi":"10.1093/jleuko/qiae208","DOIUrl":"10.1093/jleuko/qiae208","url":null,"abstract":"<p><p>Most genetically modified mice have been produced using 129 strain-derived embryonic stem cells. Despite ample backcrosses with other strains, these may retain characteristics for 129 passenger mutations, leading to confounding phenotypes unrelated to targeted genes. Here we show that widely used Ackr1-/-129ES mice have approximately 6 Mb of the 129-derived genome retained adjacently to the Ackr1 locus on chromosome 1, including several characteristic polymorphisms. These most notably affect the expression of PYHIN and Fc-gamma receptor genes in myeloid cells, resulting in the overproduction of IL-1β by activated macrophages and the loss of Fc-gamma receptors on myeloid progenitor cells. Therefore, caution is warranted when interpreting Ackr1-/-129ES mouse phenotypes as being solely due to the ACKR1 deficiency. Our findings call for a careful reevaluation of data from previous studies using Ackr1-/-129ES mice and underscore the limitations and pitfalls inherent to mouse models produced using traditional genetic engineering techniques involving 129 embryonic stem cells.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348323","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}