Journal of Leukocyte Biology最新文献_第6页

Berbamine promotes autophagy and GPX4 expression through inducing abundant ROS to restrict HIV-1 and Mtb coinfection in macrophages. Berbamine通过诱导大量ROS抑制巨噬细胞中HIV-1和Mtb的共感染，促进自噬和GPX4的表达。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf095

Xuefeng Zhou, Su Zhang, Min Ou, Hong Tao, Tingzhi Cao, Lin Li, Guoliang Zhang, Hongzhou Lu

{"title":"Berbamine promotes autophagy and GPX4 expression through inducing abundant ROS to restrict HIV-1 and Mtb coinfection in macrophages.","authors":"Xuefeng Zhou, Su Zhang, Min Ou, Hong Tao, Tingzhi Cao, Lin Li, Guoliang Zhang, Hongzhou Lu","doi":"10.1093/jleuko/qiaf095","DOIUrl":"10.1093/jleuko/qiaf095","url":null,"abstract":"Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium tuberculosis (Mtb) co-infection poses a significant public health threat, characterized by a high mortality rate due to impaired host immune responses. In this study, we investigated the role of autophagy, primarily using macrophage cell models co-infected with HIV-1 and Mtb. Our findings indicate that HIV-1 infection or latency significantly suppresses autophagy in macrophages, thereby creating a permissive environment for the survival and replication of intracellular Mtb. Co-infection experiments demonstrated that Mtb exacerbates the autophagy suppression induced by HIV-1, further promoting bacterial proliferation. Notably, pharmacological activation of autophagy using berbamine (BBM), a natural compound, significantly reduced HIV-1 latency reactivation and decreased the intracellular Mtb burden. Colocalization of LC3 with the HIV-1 capsid protein p24 and Mtb was observed using a confocal microscope. Mechanistic investigations revealed that BBM-induced autophagy is mediated by elevated levels of cytosolic reactive oxygen species (ROS), which trigger autophagosome formation and lysosomal degradation. However, prolonged ROS elevation poses a risk of cellular damage; thus, BBM concurrently upregulates the antioxidant enzyme glutathione peroxidase 4 (GPX4) to alleviate oxidative stress and maintain redox homeostasis. These findings underscore autophagy as a dual-function mechanism that restricts both viral persistence and bacterial survival during co-infection. This study highlights the therapeutic potential of targeting the crosstalk between autophagy and ROS to manage HIV-1-Mtb co-infection and suggests BBM as a promising candidate for further preclinical evaluation. These insights may inform the development of host-directed therapies aimed at improving clinical outcomes in co-infected patients.","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":"144528245","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

Caging giants: Characterizing the molecular mechanisms of neutrophil swarming against Candida albicans hyphae. 笼巨人：中性粒细胞聚集对抗白色念珠菌菌丝的分子机制。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf082

Tasha K Phillips, Kelsey Lawson, Tammy R Ozment, Allison Scherer, Alex Hopke

{"title":"Caging giants: Characterizing the molecular mechanisms of neutrophil swarming against Candida albicans hyphae.","authors":"Tasha K Phillips, Kelsey Lawson, Tammy R Ozment, Allison Scherer, Alex Hopke","doi":"10.1093/jleuko/qiaf082","DOIUrl":"10.1093/jleuko/qiaf082","url":null,"abstract":"Neutrophils utilize many mechanisms to restrict fungal growth. When phagocytosis occurs, neutrophils can create many toxic antimicrobials including reactive oxygen species and the products of myeloperoxidase. If a pathogen is too large to phagocytose, neutrophils can also resort to the release of neutrophil extracellular traps or it can engage in the behavior of \"swarming,\" in which the recruitment and antimicrobial action of many neutrophils are coordinated against a single target. Here we optimized an assay to study the behavior of swarming directly against live Candida albicans hyphae. We find that hyphae are highly potent targets for inducing swarming behavior and that swarming is very effective at restricting hyphal growth. We provide insight into the initial interactions between the pioneer neutrophil and the hyphae, including information on how fast signaling is initiated following neutrophil binding, how far neutrophils stretch before signaling occurs, and how the calcium signaling waves are unique in response to hyphal targets. We also find distinct and important roles for myeloperoxidase, spleen tyrosine kinase, Bruton's tyrosine Kinase, and CD18 in an effective neutrophil swarming response.","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/PMC12256248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234355","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

The role of tumor-associated neutrophils in the pathogenesis of recurrent respiratory papillomatosis. 肿瘤相关中性粒细胞在复发性呼吸道乳头状瘤病发病机制中的作用。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf055

Yang Xiao, Zijie Niu, Lijing Ma, Jun Wang

{"title":"The role of tumor-associated neutrophils in the pathogenesis of recurrent respiratory papillomatosis.","authors":"Yang Xiao, Zijie Niu, Lijing Ma, Jun Wang","doi":"10.1093/jleuko/qiaf055","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf055","url":null,"abstract":"Neutrophils are known to infiltrate various tumor tissues extensively and contribute to disease progression. However, the role of tumor-associated neutrophils in the pathogenesis of recurrent respiratory papillomatosis remains unclear. This study aimed to explore the prognostic significance of tumor-associated neutrophils and examine their role in the pathogenesis of recurrent respiratory papillomatosis. Immunohistochemistry was employed to assess the intensity of neutrophil infiltration in RRP tumor tissues. Multifactorial logistic regression analysis was conducted to evaluate the relationship between tumor-associated neutrophils and patient prognosis. Flow cytometry analysis was used to examine the phenotype of neutrophils. Additionally, coculture assays were performed with tumor-associated neutrophils and peripheral T cells to assess their functional interactions. Immunohistochemical analysis revealed that patients with recurrent respiratory papillomatosis exhibited significantly higher neutrophil densities within tumor tissues. Elevated neutrophil counts, neutrophil-to-lymphocyte ratio, and tumor-associated neutrophil infiltration were observed in patients with more aggressive forms of recurrent respiratory papillomatosis. Multivariate logistic regression identified the extent of neutrophil infiltration as an independent risk factor for an aggressive clinical course in these patients. Furthermore, tumor-associated neutrophils expressed high levels of CXCR1, CXCR2, and arginase 1, indicating a protumor phenotype, along with elevated levels of PD-L1, an immunosuppressive molecule. Functionally, these tumor-associated neutrophils effectively suppressed T-cell proliferation, activation, and cytokine secretion. Thus, tumor-associated neutrophils play a crucial role in fostering an immunosuppressive microenvironment that enables tumor immune evasion. This process initiates a positive feedback loop, where tumor cells secrete chemokines to recruit more neutrophils, thereby further accelerating tumor progression.","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":"144626561","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

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

Myeloid-specific deficiency of ribosomal protein L13a alters macrophage polarity and diversity during differentiation from bone marrow. 骨髓特异性核糖体蛋白L13a缺乏改变巨噬细胞在骨髓分化过程中的极性和多样性。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf102

Antara Roy, Victoria A Bzdak, Moonmoon Sinha, Anton A Komar, Peng Jiang, Barsanjit Mazumder

{"title":"Myeloid-specific deficiency of ribosomal protein L13a alters macrophage polarity and diversity during differentiation from bone marrow.","authors":"Antara Roy, Victoria A Bzdak, Moonmoon Sinha, Anton A Komar, Peng Jiang, Barsanjit Mazumder","doi":"10.1093/jleuko/qiaf102","DOIUrl":"10.1093/jleuko/qiaf102","url":null,"abstract":"Macrophages show substantial plasticity, leading to a diverse population of these cells with different states of polarization during differentiation from bone marrow. However, the mechanisms underlying this process are not well understood. Here, we identified a novel role of ribosomal protein L13a previously shown to be engaged in the physiological control of inflammation regulating macrophage diversity and polarity. Using an ex-vivo differentiation model of bone marrow-derived macrophages (BMDM) from the control (L13aflox/flox) and myeloid-specific L13a KO (L13aflox/flox LysMCre+) mice (L13a-KO), we present compelling evidence of the role of L13a in regulating macrophage polarization that goes beyond the M1-M2-based binary concept. We show that macrophages from L13a-KO mice lead to enhanced expression of classical markers of both M1 and M2 and surprising deviation from the expected response under known inducers of polarity. The phosphorylation-dependent activation of a number of signaling molecules played a role in this process. Bulk RNA and single-cell RNA sequencing of the BMDM from the L13a-KO mice show widespread change in overall gene expression and robust differences in the diverse populations of the bone marrow-derived cells from the control and KO mice. In addition, this study also shows a substantial increase of Th1 and Th2 signature genes in CD4+ T cells isolated from the L13a-KO animals. Together, our studies provide new insights into the regulations of macrophage polarization by L13a-driven novel intermediate effectors or mediators.","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":"144591401","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

Resolution of innate immune cells with proresolving lipid mediators in idiopathic pulmonary fibrosis. 先天免疫细胞与促溶解脂质介质在特发性肺纤维化中的溶解

IF 3.1 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf100

Yuet Ang, Ashton J K Ng, Wupeng Liao, K Y Kevin Wong, W S Fred Wong, Hong Yong Peh

{"title":"Resolution of innate immune cells with proresolving lipid mediators in idiopathic pulmonary fibrosis.","authors":"Yuet Ang, Ashton J K Ng, Wupeng Liao, K Y Kevin Wong, W S Fred Wong, Hong Yong Peh","doi":"10.1093/jleuko/qiaf100","DOIUrl":"10.1093/jleuko/qiaf100","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive incurable lung disease characterized by chronic inflammation and fibrosis, with innate immune cells such as neutrophils and macrophages playing central roles in its pathogenesis. This review explores the involvement of these immune cells in the inflammatory process of IPF, focusing on their contribution to disrupted tissue repair and impaired resolution. The balance between host defense mechanisms, including leukocyte recruitment, and the release of proresolving mediators is crucial for maintaining healthy tissue function and returning to preinflammatory states. We highlight the importance of inflammation resolution to prevent an overactive immune response, which can lead to irreversible fibrosis. Specialized proresolving mediators, including lipoxins, resolvins, protectins, and maresins, are discussed in terms of their regulatory effects on neutrophils and macrophages in IPF. These mediators exhibit potent anti-inflammatory actions, which can modulate the immune response and promote the resolution of inflammation. Overall, this review underscores the significance of immune modulation in IPF, with a focus on the therapeutic potential of specialized proresolving mediators in controlling the inflammatory response and preventing fibrosis progression. Future research into the antifibrotic properties of SPMs and their impact on innate immune cell regulation holds promise for novel therapeutic strategies in IPF treatment.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553706","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

Metainflammation alters neutrophil function and migration in vivo in response to tissue injury. 间皮炎改变中性粒细胞功能和迁移在体内响应组织损伤。

IF 3.1 3区医学

Journal of Leukocyte Biology Pub Date : 2025-07-09 DOI: 10.1093/jleuko/qiaf094

Cassia Michael, Joaquín Cantón-Sandoval, María Feliz-Norberto, Pablo Scharf, Sofia de Oliveira

{"title":"Metainflammation alters neutrophil function and migration in vivo in response to tissue injury.","authors":"Cassia Michael, Joaquín Cantón-Sandoval, María Feliz-Norberto, Pablo Scharf, Sofia de Oliveira","doi":"10.1093/jleuko/qiaf094","DOIUrl":"10.1093/jleuko/qiaf094","url":null,"abstract":"Overnutrition and the consumption of Western-type diets lead to chronic low-grade systemic inflammation (ie metainflammation) and a dysfunctional immune response. Although neutrophils are affected by metainflammation, mechanistic evidence regarding the direct effects of dietary fat exposure on neutrophil function and migration in vivo, particularly in response to injury, remains limited. Here, we investigated how metainflammation induced by a high-cholesterol diet (HCD) influences neutrophil function and migration following tissue injury. We employed a tailfin transection model in juvenile zebrafish larvae with fluorescently tagged neutrophils fed an HCD and assessed neutrophil function and migration dynamics in vivo at the injury site and whole animal. We combined long-term, noninvasive intravital confocal microscopy with computational analysis to examine neutrophil behavior, and photoconversion techniques to track neutrophil mobilization across the larvae. Exposure to HCD resulted in a dysfunctional neutrophil response characterized by exacerbated recruitment, increased reactive oxygen species production and NETosis, impaired apoptosis, and delayed inflammation resolution. Neutrophil forward and reverse migration were also significantly impacted at the injury site. Moreover, we identified diet-inflamed regions such as the liver and intestine as sources of activated neutrophils that reverse migrate and respond to injuries at distant sites, contributing to interorgan transmission of inflammation. Finally, ameliorating steatosis and systemic chronic inflammation rescued the exaggerated neutrophil recruitment to injury. Overall, our study highlights the crucial role of neutrophil dysregulation and reverse migration from diet-induced inflamed tissues in driving exacerbated and dysfunctional inflammatory responses to injury, providing insight into potential therapeutic strategies to alleviate these effects in metabolic disease context.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484754","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