Journal of Leukocyte Biology最新文献

{"title":"Cumulative expression of the two Lyn isoforms creates a threshold for macrophage signaling in the absence of receptor engagement.","authors":"S Erandika Senevirathne, Siyu Jin, Carter E Sellner, Silvia Toledo Ramos, Tanya S Freedman","doi":"10.1093/jleuko/qiag133","DOIUrl":"10.1093/jleuko/qiag133","url":null,"abstract":"<p><p>It has been unclear whether phenotypic differences between LynA- and LynB-knockout mice, each expressing only one splice form of the Src-family kinase (SFK) Lyn, are due to isoform-specific functions or dose effects from differences in overall Lyn expression. To assess the functions of LynA and LynB, we generated a genetic series in which LynA and LynB expression levels vary independently, allowing us to test whether upregulation of one Lyn isoform could compensate for loss of the other. We used macrophages from this dose series to test signaling at steady state and in response to pharmacological pan-SFK activation. We found that LynA and LynB are equally capable of phosphorylating the positive-regulatory tyrosine kinase Syk and the negative-regulatory inositol phosphatase SHIP1, to a level determined by the cumulative expression level of LynA + LynB protein at steady state. Despite the dependence of steady-state and induced phosphorylation of upstream signaling intermediates on the level of Lyn expression, Erk and Akt signaling in response to pan-SFK activation is enabled by any Lyn expression, insensitive to further upregulation of either isoform. Thus, expression of either LynA or LynB at steady state leads to balanced potential for positive-regulatory and negative-regulatory signaling, setting a maximal response in the absence of a microbial encounter.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110828","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":"Beyond proteostasis: the HSF1-Hsp axis in inflammation.","authors":"Gerardo E Ortiz, Rodrigo Reyes-Ramírez, Abel Soto-Machuca, Francisco A Romero, Felipe Novoa, Alexis M Kalergis, Hernán F Peñaloza, Susan M Bueno, Pablo A González","doi":"10.1093/jleuko/qiag115","DOIUrl":"10.1093/jleuko/qiag115","url":null,"abstract":"<p><p>Inflammation is a multifaceted response involving molecular and cellular components triggered by diverse stimuli, including physical, chemical, and biological factors. The connection between these stimuli and inflammatory cellular responses involves numerous interactions among molecular components, resulting in cell outputs that can either help resolve potential harmful outcomes or amplify them, leading to further complications. Notably, heat shock factor 1 (HSF1), a transcription factor primarily associated with cellular responses to elevated temperatures, has also been reported to play a key role in modulating inflammation. Indeed, growing evidence suggests a close relationship between HSF1 and intracellular signaling pathways that regulate the secretion of inflammatory cytokines, impacting both infectious and non-infectious diseases. Furthermore, chaperone proteins known as heat shock proteins (Hsps), which HSF1 transcriptionally regulates, also play important roles during inflammation by modulating numerous host factors involved in this process. Here, we examine the interplay between HSF1 and Hsps in the context of inflammation caused by infectious and non-infectious diseases. We also discuss the potential benefits of targeting these factors as strategies for reducing the effects of exacerbated or damaging inflammation.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794192","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":"From sentinels to soldiers: tissue-resident cells for next-generation immunotherapy.","authors":"Nahuel Ko, Diego Esperante, Fátima Mendoza-Roldan, Emilia Schneider-Revueltas, Aaron Jimenez-Miranda, Samira Muñoz-Cruz, Laura C Bonifaz, Julián A Gajón","doi":"10.1093/jleuko/qiag102","DOIUrl":"10.1093/jleuko/qiag102","url":null,"abstract":"<p><p>Tissue-resident immune cells are specialized populations that survey peripheral tissues independently of circulating input. Their strategic positioning, persistence, and capacity for rapid local response make them key mediators of durable antitumor immunity. Although this biology has been most extensively defined in CD8⁺ tissue-resident memory T (TRM) cells, tissue residency is increasingly recognized as a broader principle of peripheral immunity, extending to CD4⁺ TRM cells, tissue-resident NK cells, and myeloid populations. This review provides an integrative framework tracing tissue-resident biology from its ontogeny to its therapeutic frontier. We propose that TRM differentiation is shaped by the interplay between priming signals and tissue niches, with priming generating residency-poised states that are resolved into stable phenotypes by local tissue cues. We encompass a framework of canonical niches across barrier and nonbarrier tissues, identify shared instructive axes, and extend this classification to noncanonical reservoirs such as bone marrow. We further examine the metabolic dimension of tissue residency: fatty acid oxidation, purinergic adaptation, and hypoxic specialization as an active and instructible program with direct manufacturing implications for cellular immunotherapy. We propose tumors as pathological noncanonical niches in which the mechanisms of tissue retention are preserved but the effector identity is lost, and address how TRM cells nonetheless emerge as critical determinants of immunosurveillance and checkpoint blockade responsiveness. We conclude that integrating tissue-residency principles into next-generation immunotherapy is not a minor refinement but a necessary shift to achieve durable responses in solid tumors.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562295","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":"Circulating platelet-natural killer cell complexes are elevated in people living with human immunodeficiency virus on antiretroviral therapy.","authors":"Brita Ostermeier, Amber Douglass, Tomas Raul Wiche Salinas, Sanchita Pandey, Cheryl Clarkson-Paredes, Gregory M Cresswell, Anastas Propratiloff, Marc Siegel, Conrad Russell Y Cruz, Mirko Paiardini, Sanjay B Maggirwar","doi":"10.1093/jleuko/qiag116","DOIUrl":"10.1093/jleuko/qiag116","url":null,"abstract":"<p><p>Natural killer (NK) cells stand as a critical pillar in the innate immune defense against viral infections, particularly human immunodeficiency virus (HIV). However, during HIV infection, NK cells demonstrate profound dysfunction, undermining effective immune control and accelerating disease progression along with viral persistence. Understanding the mechanisms driving NK cell dysfunction is essential for the development of innovative therapeutic strategies. This study reveals a significant increase in circulating platelet-NK cell complexes (PNKCs) in individuals living with HIV (PWH) on antiretroviral therapy (ART) compared to those without HIV. PWH exhibited distinct NK cell phenotypes within PNKCs, characterized by elevated levels of CD25, interferon-gamma (IFN-γ), and natural killer group 2, member D (NKG2D), alongside decreased NKp46, relative to NK cells not engaged in complexes with platelets (non-PNKCs). Moreover, the sustained presence of platelets, or PNKCs, during in vitro NK cell expansion resulted in a heightened population of NK cells exhibiting an activated phenotype. In simian immunodeficiency virus-infected Rhesus macaques, PNKC levels were positively correlated with both plasma and cerebrospinal fluid viral loads, underscoring the role of PNKCs in disease progression. Notably, this correlation diminished following monoclonal antibody treatment with inclacumab, which inhibits P-selectin-dependent platelet interactions. We propose that the chronic activation of platelets during HIV infection fosters platelet interactions with NK cells in PWH on ART, ultimately contributing to NK cell dysfunction.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794217","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":"Correction: DLL4+ neutrophils induce alveolar macrophages to cause ADAM-17-mediated endothelial barrier disruption and the increase of ICAM1hiCXCR1lo neutrophils in sepsis.","authors":"","doi":"10.1093/jleuko/qiag124","DOIUrl":"10.1093/jleuko/qiag124","url":null,"abstract":"","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"118 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016714","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 transcription factor NF-Y promotes myeloid cell survival and protects from inflammatory vascular disease.","authors":"Carlos Silvestre-Roig, José M González-Granado, Collins Osei-Sarpong, Eva Gricar, Pilar Gonzalo, Merieme Farjia, Mariano Malamud, Lina-Marie Vöcking, Noelia Alonso-Gonzalez, Raphael Chevre, Vanesa Esteban, Vicente Andrés","doi":"10.1093/jleuko/qiag113","DOIUrl":"10.1093/jleuko/qiag113","url":null,"abstract":"<p><p>Myeloid cells orchestrate vascular inflammation through transcriptional programs that control their maturation, effector function, and survival. While lineage-determining transcription factors establish myeloid identity, our understanding of the transcriptional regulation of myeloid cell behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation and is essential for maintaining stem and progenitor cell fitness. Here, we investigate NF-Y activity in myeloid cell function and survival using integrated single-cell transcriptomics and myeloid-specific deletion of the NF-YA subunit. At RNA level, NF-Y subunit transcripts were detected across myeloid compartments, with NF-YA enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low NF-YA levels were associated with macrophages exhibiting lipid-handling and phagocytic signatures and with neutrophils displaying a proinflammatory phenotype. NF-Y deficiency impaired neutrophil adhesion and rolling, increased their susceptibility to apoptosis, and promoted activation and lipid accumulation in macrophages. In vivo, myeloid NF-YA deficiency reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, leading to larger and more unstable atherosclerotic lesions, and aggravated both atherosclerosis and injury-induced neointimal thickening. These findings identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761141","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":"New approach methodologies complement but cannot replace animal models in critical care medicine research.","authors":"Marlene E Starr, Matthew D Taylor, Longxiang Su, Atsushi Murao, Steve J Schwulst, James A Lederer, Max Brenner","doi":"10.1093/jleuko/qiag108","DOIUrl":"10.1093/jleuko/qiag108","url":null,"abstract":"<p><p>Critical care research focuses on life-threatening conditions such as sepsis, trauma, hemorrhage, and burn injury, which account for millions of hospitalizations and hundreds of thousands of deaths annually in the United States alone. Recent policy initiatives by the US Food and Drug Administration and the National Institutes of Health have promoted new approach methodologies, including organoids, organ-on-chip platforms, and computational models, as alternatives to animal research. While new approach methodologies offer valuable tools for mechanistic investigation and screening applications, this review examines whether current new approach methodology technologies can adequately replace animal models in critical care research. Critical illness involves the whole organism, including dynamic organ-organ interactions, immune-microbiome crosstalk, and adaptive systemic feedback loops. By examining major domains in critical care research and targeted organ injuries, it becomes clear that while new approach methodologies excel at interrogating isolated subsystems, they cannot currently replicate integrated physiological responses. Animal models remain essential for questions requiring assessment of multiorgan dysfunction, therapeutic safety evaluation, and clinically relevant disease trajectories. Premature policy shifts away from animal research will impede advances in critical care medicine. This review proposes a \"methodological pluralism\" approach that integrates new approach methodologies with appropriately designed animal studies through harmonized endpoints and reverse-translation frameworks. Recommendations include continued refinement of animal models to better represent the heterogeneity of human populations, adoption of quality standards for preclinical research, and strategic deployment of both new approach methodologies and animal models based on fit-for-purpose criteria. We believe this approach will satisfy ethical considerations, scientific rigor, and public health needs in critical care research.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669875","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":"MyD88 promotes neutrophil extracellular trap formation and gut leakiness after ethanol and burn injury.","authors":"Xiaoling Li, Mary Grace Murray, Marisa E Luck, Suhail Akhtar, Abigail R Cannon, Mashkoor A Choudhry","doi":"10.1093/jleuko/qiag118","DOIUrl":"10.1093/jleuko/qiag118","url":null,"abstract":"<p><p>Myeloid differentiation primary-response protein 88 (MyD88), an adapter protein used by many Toll-like receptors (TLRs), plays a critical role in initiating inflammatory responses. We previously showed that alcohol intoxication combined with burn injury causes intestinal tissue damage and leakiness. This is accompanied by increased intestinal neutrophil infiltration along with bacterial abundance and translocation. An overgrowth of bacteria can activate TLRs on intestinal epithelial cells (IECs), promoting inflammation and subsequent gut-tissue damage. To examine the role of MyD88 in intestine inflammation/leakiness after ethanol and burn injury, we used MyD88-/- mice. MyD88 deficiency in mice prevented the increases in interleukin-6 and keratinocyte-derived chemokine levels, myeloperoxidase activity, as well as the expression of neutrophil mediators Lipocalin2, S100a8, and S100a9 in the intestine. It also attenuated neutrophil extracellular trap formation and release of superoxide anion. In addition, MyD88 deficiency improved tight junction protein expression, namely that of ZO-1, OCLN, CLDN4, and CLDN8. Finally, using IEC-knockout MyD88-/- mice, we further found that MyD88 deficiency mitigated intestinal permeability after ethanol and burn injury. Together, these findings suggest MyD88 plays a critical role in intestinal inflammation and barrier leakiness after ethanol and burn injury. Therefore, targeting the MyD88 pathway may have therapeutic potential for intervention in burn injury.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850926","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":"Mouse NK cell functional maturation is dependent on MHC I.","authors":"Capucine Bourel, Félix Lombard-Vadnais, Sarah Pasquin, Sylvie Lesage","doi":"10.1093/jleuko/qiag114","DOIUrl":"10.1093/jleuko/qiag114","url":null,"abstract":"<p><p>NK cells effectively eliminate infected cells or tumor cells. The acquisition of cytotoxic functions occurs throughout NK cell functional maturation, a process that is commonly defined by the sequential expression of CD27 and CD11b. In addition, NK cell cytotoxicity is finely tuned by the process of education, which is dependent on MHC I. Expression of effector molecules is not impaired in NK cells from MHC I-deficient mice, but their cytotoxic activity towards target cells is reduced. While the role of MHC I on NK cell education has been extensively studied, its impact on NK cell functional maturation has not been defined. Using 2 distinct MHC I-deficient mouse models, we confirm that MHC I is not required for expression of effector molecules by NK cells. However, based on CD27 and CD11b expression, we find that fewer NK cells reach the final stage of NK cell functional maturation. Moreover, in β2m-deficient mice, early-stage NK cells express higher levels of granzyme B. Together, these findings demonstrate that NK cell functional maturation is dependent on MHC I and that the expression of effector proteins can be uncoupled from the NK cell functional maturation stages.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712584","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":"Kmt2c and Kmt2d histone methyltransferase deficiencies compromise macrophage function.","authors":"Burcu Al, Yerin Jung, Yubell P Alvarez, Alice Scarpa, Arslan Hamid, Younghoon Jang, Kai Ge, Elena de Domenico, Marc D Beyer, Heike Weighardt, Irmgard Förster, Thomas Ulas, Mihai G Netea, Katarzyna Placek","doi":"10.1093/jleuko/qiag110","DOIUrl":"10.1093/jleuko/qiag110","url":null,"abstract":"<p><p>Methylation of histone (H) 3 lysine (K) 4 (H3K4) has a well-established role in innate immune responses, but the contribution of H3K4 methyltransferases Kmt2c and Kmt2d in innate immunity is incompletely understood. Using conditional knockout mouse models, we investigated how Kmt2c- and Kmt2d-deficiencies affect innate immune cell function. Through functional, transcriptomic, and metabolic analyses, we delineate the consequences of disrupted epigenetic regulation on macrophage biology. Our findings reveal that loss of Kmt2c or Kmt2d in macrophages leads to impaired pro-inflammatory cytokine response and phagocytotic capacity, as well as skewed energy metabolism toward glycolysis, highlighting the critical role of H3K4 methylation-dependent chromatin regulation in shaping innate immune cell behavior. This study provides the first comprehensive characterization of innate immune system dysfunction in mouse models with conditional Kmt2c and Kmt2d deletions and offers mechanistic insight into how epigenetic regulators control fundamental immune processes.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706813","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}