Journal of Leukocyte Biology最新文献

Antibody-secreting cells (ASCs) provide the foundation for protective humoral immunity following infection or vaccination. Recent advances have revealed substantial phenotypic complexity within the ASC compartment, associated with diverse functional states and differentiation stages. Epithelial cell adhesion molecule (EpCAM, CD326) has emerged as a marker of mature plasma cells. However, the functional significance of EpCAM in B cells and ASCs remains unclear. Here, we performed an extensive analysis of EpCAM expression throughout the murine B cell lineage, revealing notable EpCAM expression in marginal zone and B1 B cells, with a progressive and significant increase during maturation of ASCs. Following activation in vitro, EpCAM exhibited biphasic induction dynamics, with early and rapid upregulation in response to B cell receptor stimulation and a delayed but sustained expression during plasmablast differentiation. To define EpCAM's functional relevance, we generated B cell-specific EpCAM knock-out mice. Remarkably, deletion of EpCAM did not alter B cell activation, proliferation, or differentiation into plasmablasts in vitro. Moreover, EpCAM-deficient mice showed normal numbers and distributions of B cell subsets and ASCs, along with unchanged serum immunoglobulin abundances. Thus, despite its dynamic regulation and restricted expression pattern, EpCAM is dispensable for B cell activation, ASC differentiation, and maintenance of ASC populations.

Pediatric burn injury induces concurrent systemic inflammation and immune dysfunction, which is associated with adverse clinical outcomes (e.g. infections). For that reason, immunomodulating therapies, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), have been of great interest to augment the immune response following burn injury. Our goal was to explore the effectiveness of GM-CSF after burn injury using a well-established, clinically relevant, juvenile mouse model of scald burn injury with bacterial infection. GM-CSF was administered intraperitoneally 3 d post-burn injury followed by a subcutaneous Pseudomonas aeruginosa inoculation at the burn wound site on post injury day 4. Seven days post-burn injury, spleen, lung, blood, and burn tissue samples were obtained to assess number of leukocytes, local and systemic cytokine concentrations, soluble protein concentrations, and bacterial clearance. Burn injury with Pseudomonas infection resulted in increased proinflammatory cytokine levels systemically and within the local burn wound and increased systemic soluble B and T lymphocyte attenuator concentrations while it decreased systemic CD27 and immune cells compared with burn alone. Treatment with a single dose of GM-CSF given prior to infection effectively ameliorated inflammation and soluble B and T lymphocyte attenuator, increased innate immune cells, decreased bacterial load, and indicated an increased wound healing environment compared with those mice who did not receive treatment. These findings provide early evidence that GM-CSF may represent a viable treatment option to improve clinical outcomes after pediatric burn injury.

Eosinophils play an important role in mediating itch and inflammation in dermatitis. The role of the eosinophil granule protein eosinophil peroxidase (EPX) in mediating inflammation and itch was tested in a dermatitis mouse model. Mice were sensitized to trimellitic anhydride (TMA) and subsequently challenged chronically on the ear to establish dermatitis. Loss of EPX (in EPX-/- mice) or blocking EPX with the drug resorcinol significantly reduced dermatitis in mice exposed to TMA. Resorcinol also reduced levels of thymic stromal lymphopoietin protein (TSLP) in skin. Further studies showed that EPX increased different cytokines in keratinocytes in cell culture via 2 distinct mechanisms. EPX-induced TSLP expression requires lysophosphatidic acid signaling while EPX-induced expression of TNF-α, CSF2, CSF3, and IL1a required IL-1 signaling. We also showed that blocking IL-1 reduced inflammation in skin following TMA exposure in mice. Thus, EPX is an important mediator of inflammation and itch, that are mediated via at least 2 pathways. This suggests that both EPX and its signaling pathways may provide novel therapeutic strategies in dermatitis.

Extracellular vesicles (EVs) are essential components for intercellular communication, bioactive cargo trafficking, and homeostasis maintenance. The knowledge regarding the diverse functions and applications of EVs has continually expanded over the recent decade. The classification of eukaryotic EVs based on their biophysical or biochemical properties has failed to adequately capture the variety of biological effects attributed to these micro- and nanovesicles. In this review, we specifically discuss the functional definition of EVs which possess decoying capabilities, including consequential biological interactions with toxins, pathogen- and damage- associated molecular patterns, and nutrients. We focus on the reported studies that highlight recent discoveries involving decoy EVs that intercept host immunity, further focusing on microbial pathogeneses as well as on chronic illnesses. Last, we evaluate biomedical methodologies to suitably address research questions and uncover distinct decoying properties of these decoy EVs across various health and disease experimental settings.

Arthritis imposes a substantial global burden and remains without curative therapy. Among the most prevalent forms, rheumatoid arthritis and osteoarthritis differ in etiology but converge on pathogenic tumor necrosis factor α (TNFα) signaling. A key regulatory node is TNFR2, which promotes immunomodulation and tissue repair in contrast to the proinflammatory signaling of TNFR1. Progranulin (PGRN), a high-affinity TNFR2 ligand, protects joints by orchestrating macrophage plasticity and chondrocyte metabolism. Central to this pathway is the adaptor protein 14-3-3ε, an essential intracellular component of the PGRN/TNFR2 complex. In macrophages, 14-3-3ε directs PI3K/Akt-mTOR signaling to restrain NF-κB and promote C/EBPβ-driven M2 polarization, while in chondrocytes it enables ERK/Elk-1 activation to sustain anabolism. Across inflammatory and degenerative models, genetic loss of PGRN, TNFR2, or 14-3-3ε abolishes protection, whereas recombinant PGRN or the engineered PGRN-derived molecule Atsttrin attenuates arthritis, preserves cartilage, and enhances bone repair. Incorporation of Atsttrin into biomaterials such as hydrogels and 3D-printed scaffolds further augments efficacy and durability in preclinical studies. This review briefly summarizes current evidence positioning the PGRN/TNFR2/14-3-3ε complex as a shared mechanism in rheumatoid arthritis and osteoarthritis pathogenesis and repair, and highlights translational opportunities-from TNFR2 agonism to Atsttrin-based therapeutics-for disease modification in arthritis.

Changes in specific immune cell lineages, such as T and B cells, play a central role in the pathogenesis of rheumatoid arthritis (RA). However, a comprehensive evaluation of systemic immune cell changes in RA remains limited. Immune cell proportions of 104 subsets across granulocyte, T-cell, B-cell, and innate lineages were profiled by flow cytometry in 21 new-onset RA patients and 21 healthy controls. Non-parametric tests compared groups, followed by training a logistic regression-based AI model with cross-validation to characterize RA immune profiles and assess each subset's contribution. Among 104 immune cell subsets analyzed, 16 were indicative of RA. Increased proportions of marginal zone B cells, IgMhi B cells, CD11b+lineage- cells, monocytes, and MHC II+ monocytes, along with decreased eosinophils, reflected activation of innate and humoral immune responses in RA patients. Elevated levels of FoxP3+CD4+ regulatory T cells (FoxP3+ CD4 Treg) and CTLA4+ CD4 Treg cells, as well as increased MHC II+CD4+ and CD8+ T cells, PD-L1+ NK cells, and PD-L1+CD8+ NKT cells, suggested a compensatory immune response. The AI model distinguished immune profiles between RA patients and healthy controls with 100% sensitivity and specificity in this dataset, identifying RA by lower MHC II+ monocytes, higher CTLA4+ CD4 Treg cells, and elevated monocytes. These findings demonstrate the potential of using ICP hallmarks to develop novel diagnostic tools and therapeutic strategies for RA.

Eosinophils are a type of white blood cell belonging to the granulocyte family. Their cytoplasm contains eosinophilic granules that hold various biologically active substances. They perform diverse functions, participating in inflammatory responses, immune defense, and tissue repair. Eosinophils are implicated in the pathogenesis of multiple diseases, including infectious diseases, allergic disorders, and hematological conditions. Moreover, increasing research in recent years has revealed significant associations between eosinophils and autoimmune diseases, solid tumors, coronary atherosclerotic heart disease, and even Alzheimer's disease. They participate in disease onset and progression through the release of toxic proteins, cytokines, and chemokines, as well as through interactions with other cells. Focusing on the biological characteristics and functions of eosinophils facilitates the elucidation of disease mechanisms associated with related disorders. This, in turn, provides further direction for eosinophil-targeted research and therapeutic strategies, including the research and development of drugs that modulate their function, targeted therapies, immunotherapies, and cell therapies. This paper provides a comprehensive review of the structure, function, and role of eosinophils in related diseases, along with potential future therapeutic strategies. It aims to deepen the understanding of researchers and clinicians, thereby facilitating their application in further research, as well as in clinical disease diagnosis and treatment analysis.

Cholesterol metabolism plays a pivotal role in gastrointestinal cancers, from fueling tumor growth, facilitating metastatic niche formation, shaping tumor immunosuppressive microenvironment, to promoting immunotherapy resistance. Paradoxically, cholesterol may also exert context-dependent protective effects. Statins, the most widely prescribed cholesterol-lowering drugs, function through inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway. Beyond their cholesterol-lowering effects and well-established safety profile, statins have demonstrated pleiotropic properties, including anti-inflammatory, antiangiogenic, and immunomodulatory effects. These additional effects have further sparked growing interest in repurposing statins for cancer treatment. Indeed, both preclinical and clinical findings have demonstrated the therapeutic efficacy of statins in gastrointestinal cancer treatment, which may function through metabolic regulation as well as immunomodulation. In this review, we focus on the translational potential of statin repurposing in gastrointestinal cancers, with particular emphasis on their roles in modulating tumor immune evasion. We also explore emerging strategies such as statin-based nanoparticle formulations designed to enhance drug delivery and synergize with immunotherapies. By integrating evidence from preclinical models, clinical cohorts, and ongoing trials, we critically assess the therapeutic potential of statins in gastrointestinal malignancies and highlight their promise as accessible, low-toxicity adjuncts in cancer treatment.

Tumor-associated macrophages (TAMs) exert both pro- and antitumoral functions that influence cancer progression and patient prognosis. However, single-cell RNA sequencing (scRNA-seq) studies have revealed that TAM heterogeneity remains incompletely characterized. By performing an unbiased, integrated in silico analyses of publicly available scRNA-seq datasets, comprising samples from blood, tumor, and nontumoral mammary tissue from both patients with breast cancer (BRCA) and healthy individuals, we identified seven transcriptional signatures corresponding to distinct TAM subsets, exhibiting unique functional profiles, including heightened interferon responses, scavenging, and matrix remodeling, the latter two being characteristic of tissue repair. Notably, none of these subsets aligned with the M1/M2 classification of macrophage (Mϕ) polarization. Interferon-associated genes were predominantly enriched in blood monocytes, whereas tissue-repair-associated signatures were more abundant in tissue-resident Mϕ, suggesting that TAMs bearing these signatures resemble monocyte-derived or tissue-resident Mϕs, respectively. Importantly, TAM subsets expressing interferon-associated genes were associated with improved survival compared to tissue-repairing TAMs in a BRCA cohort from The Cancer Genome Atlas. Additionally, one signature was heightened in peripheral monocytes from BRCA patients compared with healthy individuals, which was experimentally validated in a pilot study of Mexican BRCA patients. We concluded that these signatures are a closer description of TAM heterogeneity in BRCA.

Precursor exhausted and terminally exhausted T cells (Tpex and Tex) are associated with immune checkpoints; T-cell checkpoint blockade may improve patient survival. We assessed cytotoxic activity and PD-1/TIM-3 expressions of CD3+CD8+CD56+ T cells (NK-like T) in cytokine-induced killer (CIK) cells across exhaustion states. We grouped the NK-like T cells into 3 based on TOX and TCF1 expressions: TOX-TCF1+ (memory-like NK-like T), TOX+TCF1+ (NK-like Tpex), and TOX+TCF1- (NK-like Tex). The proportion of NK-like Tpex cells among the CIK cells was the highest (>90%) after culture. TIM-3 and PD-1 expression were high in NK-like Tpex but low in NK-like Tex cells. However, TIM-3 expression was higher than PD-1 expression in CIK cells, suggesting that combining CIK cells and TIM-3 inhibitors may have better effects. Perforin, granzyme B, DNAM-1, and NKG2D, which are cytotoxicity biomarkers, were more expressed in NK-like Tpex than in NK-like Tex cells, which implies that NK-like Tpex may still has a strong cytotoxic effect. The CD4⁺ T cell counts and TIM-3 expression level in the NK-like Tpex cells were positively correlated. CD4⁺ T cells may actively sustain progenitor exhaustion, but the mechanisms are unknown. In vitro cytotoxicity assays confirmed that CIK cell-mediated tumor cytotoxicity was significantly enhanced by TIM-3 than by PD-1 blockade. Furthermore, tumor cytotoxicity was greater for CIK cell cultures with higher than those with lower CD4⁺ T cell counts following TIM-3 blockade. This work demonstrates CD4⁺T cell modulation of progenitor exhaustion in CIK cells and positions TIM-3 blockade to rescue their antitumor potential.