Journal of Leukocyte Biology最新文献_第2页

Adaptation of the living therapeutic materials concept to the immune sensing of neutrophil granulocytes. 活体治疗材料概念对中性粒细胞免疫感知的适应。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf086

Islam Mohamed, Kristin Burckhardt, Stefan Lohse

{"title":"Adaptation of the living therapeutic materials concept to the immune sensing of neutrophil granulocytes.","authors":"Islam Mohamed, Kristin Burckhardt, Stefan Lohse","doi":"10.1093/jleuko/qiaf086","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf086","url":null,"abstract":"Neutrophils are innate immune cells that perpetually patrol the circulation and tissues. They sense and migrate toward invading microbes to initiate and orchestrate a robust immune response. Their highly reactive nature, driven by multiple and redundant receptor families recognizing bacterial components, makes them particularly sensitive to contaminants or nonsterile implants. This often leads to a neutrophil-driven foreign body reaction that shields the implant and triggers inflammation, collateral tissue damage, or even sepsis. This presents a significant challenge for living therapeutic materials, an innovative biomedical approach using genetically engineered bacteria encapsulated in natural or synthetic polymers. Since bacterial turnover inevitably releases pathogen-associated molecular patterns that activate neutrophils to mitigate or prevent a potent neutrophil response, living therapeutic material design strategies are required to protect the living therapeutic material from damage while maintaining its functionality. This review focuses on current strategies involving bacterial genetic engineering, immune-shielding materials and factors, and modified hydrogel-based systems to minimize immune recognition. Engineering the bacterial chassis to produce immune tolerance-inducing metabolites from commensals, modified pathogen-associated molecular patterns, and pathogen-associated molecular pattern-cleaving autolysins may enhance biocompatibility. A crucial aspect for clinical translation is robust biocontainment to prevent bacterial escape, ensuring living therapeutic material remains a safe and effective therapeutic platform. While the potential of the living therapeutic material concept lies in the development of tailored medicine specifically designed for a specific disease and enabling local, cost-effective, site- and stimulus-responsive treatment, balancing the neutrophil immune response remains an important milestone on the path to living therapeutic material for future biomedical applications.","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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637230","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}

引用次数: 0

Mutation in Staphylococcus aureus that supports gain of function in susceptibility both to hypochlorous acid and to human neutrophils. 支持获得对次氯酸和人类中性粒细胞敏感性功能的金黄色葡萄球菌突变。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf057

Athmane Teghanemt, Katrin Schilcher, Jeffery S Kavanaugh, Alexander R Horswill, William M Nauseef

{"title":"Mutation in Staphylococcus aureus that supports gain of function in susceptibility both to hypochlorous acid and to human neutrophils.","authors":"Athmane Teghanemt, Katrin Schilcher, Jeffery S Kavanaugh, Alexander R Horswill, William M Nauseef","doi":"10.1093/jleuko/qiaf057","DOIUrl":"10.1093/jleuko/qiaf057","url":null,"abstract":"Optimal antimicrobial action of human neutrophils (polymorphonuclear leukocytes [PMNs]) relies on the synergy of oxidants and granule proteins, most notably that between the granule protein myeloperoxidase (MPO) and hydrogen peroxide (H2O2) to oxidize chloride anion to produce the potent microbicide, hypochlorous acid (HOCl). However, despite the potency of HOCl, some ingested Staphylococcus aureus cells survive within PMNs and contribute to disease. To identify factors that support the resistance of ingested staphylococci to PMN-oxidative killing, we screened the Nebraska Transposon Mutant Library in the USA300 methicillin-resistant S. aureus strain for mutants that were more sensitive or resistant to HOCl. We identified a mutant in mazF that survived challenge with reagent HOCl better than did the parental strain. In addition, the mutant resisted killing by human PMNs, suggesting that MazF contributes to the susceptibility of S. aureus to HOCl-mediated damage, the ability of S. aureus to recover from HOCl attack, or both. To confirm the genetic basis of the MazF phenotypes, we transformed the mutant with an expression plasmid carrying the wild-type mazF gene or the empty vector control to complement the phenotype. The deletion mutant with the empty vector survived better in reagent HOCl and in PMNs than did the parental strain or the complemented deletion mutant. Taken together, these data suggest that in the absence of mazF expression, USA300 methicillin-resistant S. aureus better resisted, repaired, or both resisted and repaired the sublethal damage produced by HOCl alone or by antimicrobial elements in human PMNs.","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/PMC12239878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101953","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}

引用次数: 0

Transcriptional programs underlying human monocyte differentiation and diversity. 人类单核细胞分化和多样性的转录程序。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf058

Ravi K Komaravolu, Daniel J Araujo, Catherine C Hedrick, Ahmad Alimadadi

{"title":"Transcriptional programs underlying human monocyte differentiation and diversity.","authors":"Ravi K Komaravolu, Daniel J Araujo, Catherine C Hedrick, Ahmad Alimadadi","doi":"10.1093/jleuko/qiaf058","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf058","url":null,"abstract":"Classical monocytes (CD14hiCD16-) differentiate into intermediate monocytes (CD14+CD16+), which in turn yield nonclassical monocytes (CD14-CD16hi). To investigate the transcriptional regulation underlying this differentiation or conversion, we analyzed 3 single-cell RNA-sequencing datasets of peripheral mononuclear blood cells from healthy individuals using the single-cell regulatory network inference and clustering package. Cells were re-annotated into classical monocytes, intermediate monocytes, nonclassical monocytes, classical dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs) based on gene signatures. Regulon activity was analyzed, revealing 220 shared regulons across datasets. Distinct regulons characterized most myeloid subsets except intermediate monocytes, which appeared as a transitional state, sharing regulons with both classical and nonclassical monocytes. Regulons such as HMGB2, CREB5, and FOSB were enriched in classical monocytes, while TCF7L2 and POU2F2 were specific to nonclassical monocytes. Plasmacytoid DCs showed the greatest divergence, possessing many unique regulons, including AR and RUNX2, whereas cDCs shared more regulons with monocytes than pDCs, with RUNX1 specific to cDCs. All mononuclear phagocytes shared a common core of active regulons, including RELB, ID1, CLOCK, BACH1, and FLI1. Notably, FLI1 was expressed across all myeloid subclasses but emerged as a key regulator influencing monocyte gene regulatory networks. Pseudotime modeling using regulon activity demonstrated that monocyte conversion is a continuous process. Differential regulon analysis identified distinct biological processes that were enriched in monocyte subsets, highlighting that regulon activity analysis provides novel insights into myeloid cell biology. Our findings underscore the key role of transcriptional regulatory programs in defining mononuclear phagocyte identity and reveal novel signatures associated with monocyte diversity and differentiation.","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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591403","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}

引用次数: 0

KMT2D upregulates SMG1 via histone methylation to antagonize mTOR and reinforce DLBCL ferroptosis. KMT2D通过组蛋白甲基化上调SMG1，拮抗mTOR，增强DLBCL铁凋亡。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf092

Yongcheng Sun, Zhijuan Xu, Zanzan Wang, Yanli Zhang, Ping Zhang, Lixia Sheng, Shujun Yang, Guifang Ouyang

{"title":"KMT2D upregulates SMG1 via histone methylation to antagonize mTOR and reinforce DLBCL ferroptosis.","authors":"Yongcheng Sun, Zhijuan Xu, Zanzan Wang, Yanli Zhang, Ping Zhang, Lixia Sheng, Shujun Yang, Guifang Ouyang","doi":"10.1093/jleuko/qiaf092","DOIUrl":"10.1093/jleuko/qiaf092","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is highly heterogeneous and prone to epigenetic mutations. Non-apoptotic cell death pathways, especially ferroptosis, have become an emerging direction for cancer treatment. This project was designed to probe into the potential of histone-lysine N-methyltransferase 2D (KMT2D) in modulating DLBCL ferroptosis through epigenetic mechanisms. We employed quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) to detect the expression level of KMT2D, CCK-8 assay to measure cell viability, flow cytometry to assess cell cycle and apoptosis, and fluorescent probes to analyze lipid reactive oxygen species levels. 4-hydroxynonaldehyde (4-HNE) and malondialdehyde were detected by WB and corresponding kits to determine the degree of intracellular ferroptosis. The level of H3K4Me1 was determined by using WB and immunofluorescence. Furthermore, we verified the transcriptional regulatory relationship between KMT2D and SMG1 through bioinformatics analysis, chromatin immunoprecipitation assay. We also applied WB to assess the activation of the AKT-mTOR pathway. Finally, the in vitro experimental results were validated by qRT-PCR, WB, immunohistochemistry, and fluorescent probe detection in a xenograft tumor model constructed in BALB/c nude mice. Overexpression of KMT2D considerably repressed the malignant behavior of DLBCL and triggered ferroptosis in cells. KMT2D was able to bind directly to the promoter region of the SMG1 gene and induce the transcriptional antagonistic mTOR pathway of SMG1 through H3K4Me1, thereby inducing ferroptosis in DLBCL cells. These findings demonstrate that KMT2D reinforces ferroptosis in DLBCL by antagonizing SMG1-mediated mTOR signaling, identifying it as a novel therapeutic target.","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":"144511992","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}

引用次数: 0

A comprehensive phenome wide analysis of the role of neutrophils in health and disease. 中性粒细胞在健康和疾病中的作用的综合表型分析。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf076

Katy Fleming, Naomi Cornish, Emma E Vincent, Andrew D Mumford, Borko Amulic, Kate Burley

{"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":"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.","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}

引用次数: 0

Macrophage IL-4 polarization is restricted by soluble CD40 agonists and antigen-induced CD154 but not by constitutive CD154 expressed by CD4+ T cells. 巨噬细胞IL-4极化受可溶性CD40激动剂和抗原诱导的CD154的限制，但不受CD4+ T细胞表达的组成型CD154的限制。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf069

Mariana Suárez-Martins, Ignacio González-Alayón, Cecilia Casaravilla, Louis Boon, Pedro H Papotto, Conor M Finlay, Stephen J Jenkins, Judith E Allen, Álvaro Díaz

{"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":"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.","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}

引用次数: 0

Sex-specific leukocyte responses to peanut allergen: uncovering potential links to the molecular circadian clock. 性别特异性白细胞对花生过敏原的反应：揭示与分子生物钟的潜在联系。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf097

Santhosh Kumar Duraisamy, Isaac Kirubakaran Sundar

{"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":"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.","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}

引用次数: 0

Arginine metabolism supports metabolic reprogramming in trained immunity. 精氨酸代谢支持训练免疫的代谢重编程。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf080

Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea

{"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":"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.","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}

引用次数: 0

Neutrophil CD300ld: A savior of organ failure? 中性粒细胞CD300ld：器官衰竭的救星？

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-04 DOI: 10.1093/jleuko/qiaf101

Duane Jeansonne, Samithamby Jeyaseelan

引用次数: 0

Treponema pallidum lipoprotein TpF1 regulates METTL14-mediated NF-κB signaling pathway to promote macrophage M2 polarization. 梅毒螺旋体脂蛋白TpF1调节mettl14介导的NF-κB信号通路，促进巨噬细胞M2极化。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-03 DOI: 10.1093/jleuko/qiaf099

Qian Cao, Xiangping Zhou, Fei Zou, Rong He, Liena He, Jiajun Chen, Yue Li, Ting Cao, Yumeng Li, Xiaopeng Lan, Shuangquan Liu

{"title":"Treponema pallidum lipoprotein TpF1 regulates METTL14-mediated NF-κB signaling pathway to promote macrophage M2 polarization.","authors":"Qian Cao, Xiangping Zhou, Fei Zou, Rong He, Liena He, Jiajun Chen, Yue Li, Ting Cao, Yumeng Li, Xiaopeng Lan, Shuangquan Liu","doi":"10.1093/jleuko/qiaf099","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf099","url":null,"abstract":"During Treponema pallidum(T.pallidum) infection, m6A modification negatively regulates inflammatory responses in macrophages. However, whether m6A modification participates in the regulation of macrophage M2 polarization during T.pallidum infection remains unclear. Using THP-1-derived macrophages as a model, this study investigated the mechanism by which T.pallidum lipoprotein TpF1 promotes macrophage M2 polarization, and analyzed the effect of TpF1 on m6A modification in macrophages and the regulatory role of methyltransferase METTL14. Results showed that upon TpF1 stimulation, expression of M2 macrophage markers CD206 and PPARγ was significantly increased, and levels of anti-inflammatory factors TGF-β and CCL18 were upregulated at both mRNA and protein levels. In contrast, expression of M1 marker CD80 and pro-inflammatory factors IL-1β and TNF-α was significantly decreased at both mRNA and protein levels, indicating that TpF1 promotes macrophage polarization toward the M2 phenotype. Meanwhile, TpF1 upregulated global m6A levels in macrophages, accompanied by increased expression of m6A methyltransferase METTL14 and reader protein YTHDF2. Knocking down METTL14 with siRNA inhibited TpF1-induced elevation of global m6A levels and macrophage M2 polarization. Mechanistically, TpF1 promoted macrophage M2 polarization by activating the NF-κB pathway, as demonstrated by the inhibitory effect of NF-κB-specific inhibitors on M2 polarization. Further studies revealed that METTL14 knockdown significantly suppressed TpF1-induced NF-κB activation. These findings indicate that T.pallidum lipoprotein TpF1 promotes macrophage M2 polarization via METTL14-mediated regulation of the NF-κB signaling pathway, offering new insights into the immune evasion mechanisms of Treponema pallidum.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553756","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}

引用次数: 0