Journal of Leukocyte Biology最新文献

{"title":"Human Neutrophils are a Cellular Source of Apolipoprotein A-I.","authors":"Xianglan Yao, Joni Mills, Pradeep K Dagur, Wan-Chi Lin, Maria Lopez-Ocasio, Meixia Gao, Zu-Xi Yu, Kazuyo Takeda, Karen J Keeran, Ick Ho Kim, Amisha V Barochia, Stewart J Levine","doi":"10.1093/jleuko/qiaf104","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf104","url":null,"abstract":"<p><p>Apolipoprotein A-I (APOA1), the major protein of high-density lipoproteins, has anti-inflammatory functions. APOA1 is primarily produced in the liver, however, it is not known whether neutrophils are a cellular source. Here, we assessed whether human neutrophils express APOA1. Peripheral blood and bronchoalveolar lavage fluid (BALF) were obtained from healthy volunteers (HVs) and asthmatics. Peripheral blood neutrophils from HVs expressed APOA1 at both the mRNA and protein levels, while confocal microscopy demonstrated that APOA1 was localized to a unique population of intracytoplasmic granules. In HVs and asthmatics, APOA1 was preferentially expressed by neutrophils with high side-scatter (SSChigh) in blood and BALF. Furthermore, APOA1+ SSChigh neutrophils were characterized as a population with high levels of caspase-3/7 activation and CCR5 expression. Since APOA1 has anti-inflammatory functions, this suggests that APOA1 expression by neutrophils may represent a mechanism to attenuate excessive inflammatory responses in health and disease.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626560","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":"FAP on human NK cells: insights from NK 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":"https://doi.org/10.1093/jleuko/qiaf103","url":null,"abstract":"<p><p>Fibroblast activation protein alpha (FAP) is a post-prolyl proteolytic enzyme highly expressed in the tumor microenvironment (TME), particularly in cancer-associated fibroblasts (CAFs). Although previously thought to be restricted to CAFs, malignant cells and pathological fibroblasts, recent studies have identified FAP expression in natural killer (NK) cells. However, its expression and activity in NK cells remain poorly characterized. Here, we investigated FAP expression and activity in resting and cytokine-stimulated (IL-2 and IL-15) primary human NK cells and NK92 cells. NK cell activation resulted in a significant decrease in FAP protein expression and enzymatic activity. Treatment with the FAP inhibitor UAMC-1110 altered the expression of activating and inhibitory NK cell receptors and reduced perforin expression, though it did not impact degranulation or cytotoxic function. Culturing NK cells in CAF-conditioned medium or direct co-culture with CAFs increased FAP expression and activity in NK92 cells, with donor-dependent effects observed in primary NK cells. These conditions also led to a reduction in NK activating and inhibitory receptor expression. Furthermore, hypoxia upregulated FAP in both NK92 and primary NK cells. Overall, our findings demonstrate that FAP is downregulated in/on NK cells upon activation with IL-2 and IL-15, whereas it is upregulated under TME-mimicking conditions. This may suggest that FAP contributes to the phenotype formation of NK cells, particularly within the TME, where we hypothesize that NK cells might prioritize invasive capacity over cytotoxic capacity, thus upregulating FAP.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","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":"Microenvironmental conditions and serum availability alter primary human macrophage NF-κB inflammatory response and function.","authors":"Breana Channer, Marzieh Daniali, Lexi Sheldon, Katy Emanuel, Yash Agarwal, Taylor Kist, Brian J Murphy, Meng Niu, Will Dampier, Howard Fox, Peter J Gaskill","doi":"10.1093/jleuko/qiaf071","DOIUrl":"10.1093/jleuko/qiaf071","url":null,"abstract":"<p><p>Macrophages are central to innate immunity and are routinely used in vitro to examine molecular mechanisms contributing to innate immune signaling. However, there is a lack of consensus within the field for optimal in vitro culturing methods, and it is not well understood whether differences in culture conditions produce incongruent outcomes. Here, we compared the effects of commonly used culture medium compositions on TLR4-mediated proinflammatory activity in primary human monocyte-derived macrophages (hMDMs) isolated from healthy blood donors. hMDMs were cultured in fetal bovine serum (FBS)-containing or FBS-free conditions in either Dulbecco's Modified Eagle Medium (DMEM), RPMI, or in Macrophage-Serum Free Medium (M-SFM). Lipopolysaccharide-mediated immune response was measured through nuclear factor κB activation and cytokine and chemokine secretion, which were muted in M-SFM cultures compared with DMEM and RPMI cultures. FBS supplementation increased total cytokine secretion in response to lipopolysaccharide but also showed higher baseline secretion, suggesting a proinflammatory phenotype. Moreover, M-SFM cultures exhibited less phagocytosis compared with DMEM and RPMI cultures. Morphologic analysis of unstimulated hMDMs revealed the highest cell area and length-to-width ratio in M-SFM compared with DMEM or RPMI cultures. FBS-free and M-SFM conditions produced distinct transcriptional profiles compared with media supplemented with FBS, most notably in cell cycle pathways and lipid homeostasis, respectively. Overall, DMEM and RPMI produce comparable morphologic and functional results, albeit with some small differences, while M-SFM produces a muted inflammatory response in macrophages. These data demonstrate that in vitro microenvironment drives differential inflammatory outcomes in human macrophages and is a critical component of experimental design in this cell type.</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/PMC12239098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119631","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":"Potential functions of TRPM2 and TRPM7 channels in the tumor microenvironment.","authors":"Irma Yadira Izaguirre-Hernández, Adriana Sumoza-Toledo","doi":"10.1093/jleuko/qiaf098","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf098","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is a complex and dynamic ecosystem consisting of both cellular and non-cellular components that collectively modulate the anti-tumor immune response, as well as cancer growth, invasion, metastasis, immune evasion, and resistance to therapy. Calcium (Ca2+) and magnesium (Mg2+) are two essential ions for a wide range of cellular processes including proliferation, differentiation, migration and protein secretion. The intracellular homeostasis and spatio-temporal distribution of these two ions are tightly regulated by ion channels, notably members of the transient receptor potential melastatin (TRPM) subfamily such as TRPM2 and TRPM7. TRPM2 is a Ca2+-permeable channel activated by ADP-ribose (ADPR) and reactive oxygen species (ROS), whereas TRPM7 permeates both Ca2+ and Mg2+ ions and exhibit constitutive activity. Both channels have been involved in redox-sensitive signaling and function as temperature sensors across various physiological and pathological context, such as cancer. Here we provide an overview of the potential roles of TRPM2 and TRPM7 in regulating cellular dynamics within the TME, with a focus on their contributions to immune modulation.</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":"144600707","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":"Remembering Michael P. Cancro: modern Renaissance Man.","authors":"Mary M Tomayko, Jean L Scholz","doi":"10.1093/jleuko/qiaf079","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf079","url":null,"abstract":"","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":"144600708","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":"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":"<p><p>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.</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":"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}

{"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":"<p><p>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.</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/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}

{"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":"<p><p>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.</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":"","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}

{"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":"https://doi.org/10.1093/jleuko/qiaf102","url":null,"abstract":"<p><p>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.</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":"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}

{"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":"<p><p>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.</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":"","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}