Journal of Leukocyte Biology最新文献

Since its emergence in 2019, the study of biomarkers in COVID-19 has focused on predicting the course of this potentially fatal disease. The eosinophil-to-lymphocyte ratio (ELR) appears to be a new indicator of systemic inflammation, morbidity, and mortality in inflammatory, allergic, and cancer. The aim of our study was to determine the prognostic value of ELR and its early variation in predicting in-hospital mortality and severity in emergency department (ED) patients with SARS-CoV-2 infection. Between March 1 and April 30, 2020, we conducted a multicenter, retrospective study in 6 major hospitals in northeastern France. The cohort included patients with a confirmed diagnosis of SARS-CoV-2 infection (moderate-to-severe disease) hospitalized after admission to the ED. A total of 1,035 patients were included in this study. The ELR at 24 h (odds ratio: 0.0054; 95% confidence interval: 0.0001 to 0.2523; P = 0.008) was associated with severity of infection. The only biochemical factor significantly associated with mortality was ΔELR at 24 h (i.e. the difference between ELR values at 24 h and at admission) (odds ratio: 0.0305; 95% confidence interval: 0.0026 to 0.3626; P = 0.006) in univariate analysis. The best ELR threshold for predicting severity of infection was found with the ELR at 24 h with a result of 0.0007 (sensitivity 63.8%, specificity 61%), and for predicting mortality, ΔELR at 24 h found significant values with a threshold of -0.013 (sensitivity 77.4%, specificity 8.48%). In conclusion, ELR at 24 h after ED admission may be a potentially useful biomarker for early prediction of severity of SARS-CoV-2 infection, but its isolated use remains limited for mortality prediction.

Trained immunity amplifies innate immune responses in an antigen-independent manner. This study explored the ability of trained human primary macrophages to modulate the phenotype and function of T cells. Macrophages play an important role in antigen presentation, resulting in T-cell activation and antigen-specific clonal expansion; however, few studies have investigated whether trained immunity induction in macrophages modulates T-cell activation. Here, through surface marker analysis of naive, β-glucan-, and Bacillus Calmette-Guérin-trained macrophages, we identified 8 distinct macrophage clusters following trained immunity induction. One of these populations showed an increase in surface activation markers CD40 and CD86, as well as major histocompatibility complex molecules. In vitro co-culture of T cells with autologous Bacillus Calmette-Guérin-trained macrophages resulted in a skewing toward TH17 cells. We also observed an increase in TH17 percentage after Bacillus Calmette-Guérin vaccination of human subjects. The bias toward TH17 triggered by trained macrophages required direct T cell to macrophage contact. Trained macrophages potentiated TH17 skewing independently of the antigen presented. While co-cultures of T cells and Bacillus Calmette-Guérin-trained macrophages responded with higher production of interferon-γ and interleukin-17 after stimulation, no clear shifts toward effector or memory T cells were observed. In conclusion, this study provides evidence that Bacillus Calmette-Guérin-trained macrophages can modulate T-cell function toward a TH17 phenotype, suggesting that Bacillus Calmette-Guérin-induced trained immunity has the potential to enhance not only innate immune responses but also to modify adaptive T-cell immunity.

Megakaryocyte emperipolesis is a biological process in which a cell penetrates and exists as a viable intact cell within another. It is a recognized morphological feature of myeloproliferative neoplasms (MPNs), in which neutrophils can be seen within megakaryocytes in bone marrow smears and sections. We aimed to determine whether neutrophil contents, specifically protein and RNA, are deposited within megakaryocytes due to emperipolesis. Evaluation of hematoxylin and eosin-stained bone marrow showed that 84% of MPN patients (n = 163) had megakaryocyte emperipolesis, most notably in enlarged megakaryocytes and those with pyknotic/condensed nuclei. Morphological assessment and immunohistochemical staining for CD15-neutrophil membrane antigen confirmed that majority of intramegakaryocytic cells were neutrophils, and that emperipolesis was more frequent in myelofibrosis patients and patients with pathologic reticulin. Furthermore, megakaryocytes in MPNs were observed to have intracellular positivity for neutrophil azurophilic granule protein myeloperoxidase (MPO) (n = 21 MPN patients) and specific granule lactoferrin (n = 56). Platelets were also used as a surrogate to establish if neutrophil contents had been transferred into megakaryocytes intracellularly of MPN patients, using mass spectrometry to assess protein and transcriptomic next-generation sequencing to assess messenger RNA (mRNA). A total of 109 neutrophil mRNA transcripts and 20 neutrophil granule proteins were upregulated in platelets of MPN patients compared with control subjects, including cathepsin-G and lactoferrin, with 5.1- and 4.6-fold increase in mRNA and 1.8- and 1.4-fold protein increases, respectively. This suggests that the transfer of neutrophil material occurs during emperipolesis in disease state, which could be a consequence of neutrophil degranulation or apoptosis.

We present a novel classification system for murine thymic epithelial cells (TECs), identifying 11 distinct types, four in the thymic cortex and seven in the medulla, based on their spatial localization and unique ultrastructural features. As key stromal components of the thymic microenvironment, TECs play indispensable roles in T cell development, including thymocyte selection, antigen presentation, and structural support. Our classification spans from the subcapsular cortex to the deep medulla and incorporates microanatomical context, morphology, and functional characteristics, providing a comprehensive and flexible framework to study TEC heterogeneity in relation to thymopoiesis. Aligning with TEC classification in rats and humans, this system highlights conserved spatial organization across species while remaining adaptable for refinement. Each TEC type is distinguished by features such as chromatin organization, cytoplasmic morphology, vacuolar content, and organelle distribution, attributes that suggest distinct functional contributions to various stages of thymocyte maturation. Importantly, the classification is designed for logical expansion both horizontally (inclusion of additional subtypes within the proposed TEC types) and vertically (inclusion of entirely novel TEC types). By integrating detailed morphological observations with testable functional hypotheses, this framework underscores the essential role of TEC diversity in supporting thymic architecture and orchestrating effective T cell output. Overall, it offers a robust foundation for future research into immune development and the pathological consequences of thymic dysfunction.

Macrophages have a dual role in tissue healing after injury as they perform tissue repair functions but can also precipitate tissue damage or promote fibrosis. Platelets, beyond their role in thrombosis and hemostasis, are crucial mediators of inflammation and interact with macrophages. Platelet-macrophage interactions have been proposed to modulate macrophage phenotype, including their profibrotic functions, but the full extent of the platelet impact on the macrophage transcriptome is unknown. Here, we aimed to investigate how platelets affect macrophage activation in vitro. Using experimental myocardial infarction (MI) in mice as a model of sterile tissue injury, we readily visualized the direct interaction of platelets with macrophages in the ischemic heart using fluorescence microscopy. Bulk RNA-sequencing of mouse bone marrow-derived macrophages co-cultured in vitro with thrombin-activated platelets showed a widespread proinflammatory activation, with upregulation of genes associated with inflammation (Il1b, Trem1, Tlr2, Cd14), angiogenesis (Vegfa) and response to hypoxia (Hif1a). Resting platelets also led to activation of inflammatory gene expression by macrophages, albeit to a much lesser extent. Activated or resting platelets, or the platelet-derived chemokine CXCL4, had a limited impact on macrophage expression of profibrotic genes (Spp1, Fn1). Using a transwell assay, we further demonstrate that the proinflammatory effects of platelets on the macrophage transcriptome were largely contact dependent. Altogether, our work shows that platelets interact with macrophages in the ischemic heart and polarize macrophages towards a proinflammatory phenotype in vitro, with potential implications for cardiac macrophage inflammatory activation after acute experimental MI.

Existing studies examining the relationships among immunological cell phenotype, plasma metabolites, and pancreatic cancer susceptibility are limited. More comprehensive research is required to elucidate the complex interactions underlying these associations. Genetic instruments for 731 immune phenotypes (N = 3,757), 1,400 circulating metabolites (N = 8,299), and pancreatic cancer (N = 1,196) were derived from a genome-wide association study (GWAS) meta-analysis. A two-step, two-sample Mendelian randomization (MR) study using the Inverse Variance Weighted method was conducted to investigate the causal influence of immune cell phenotypes on pancreatic cancer and to assess the intermediary role of circulating metabolites. Sensitivity analyses were carried out to verify the robustness, potential heterogeneity, and pleiotropy. MR analyses identified protective effects of CD64 on monocyte (OR = 0.859, 95%CI: 0.802 to 0.920, P = 1.65 × 10-5, PBonferroni = 0.012) against pancreatic cancer. Moreover, 68 metabolites were suggestively associated with pancreatic cancer. Notably, mediation MR revealed that the causal role of CD64 on monocytes in pancreatic cancer was largely mediated by 1-palmitoleoylglycerol (16:1) level (OR = 0.0089, 95%CI: 0.00121 to 0.0167, P = 0.023), accounting for 5.91% of the total effect. These findings establish a causal relationship between CD64 on monocytes and pancreatic cancer, possibly operating through circulating metabolites. The research advances knowledge of the interplay between immune responses and the risk of pancreatic cancer, providing important implications for immunologically targeted treatment approaches.

Neutrophils are essential components of the innate immune system, playing a critical role in responding to infections and inflammation. Their recruitment from blood circulation to affected tissues follows a well-coordinated multistep adhesion and activation cascade. Recent studies highlight the importance of posttranslational modifications, particularly sialylation, in regulating neutrophil recruitment. Sialic acids, negatively charged monosaccharides, are attached to glycoproteins and glycolipids on neutrophil surfaces, influencing their stability, signaling, and interactions with endothelial cells. Selectins, key mediators of neutrophil rolling, recognize sialylated ligands such as sialyl Lewis-X on the neutrophil surface enabling the initial capture and rolling process. Additionally, sialylation of chemokine receptors and integrins modulate neutrophil activation and firm adhesion. Beyond recruitment, sialylation affects neutrophil homeostasis, aging, and clearance, as well as their interactions with pathogens and tumor cells. Dysregulation of sialylation has been linked to autoimmune diseases, cancer progression, and infections, making it an interesting target for therapeutic interventions. This review focuses on the functional role of posttranslational sialylation in neutrophil biology, detailing its impact on leukocyte recruitment, immune modulation, and potential therapeutic applications.

Natural killer (NK) cells represent a promising effector population for tumor immunotherapy. Conventional NK cell engagers (NKCEs), primarily targeting CD16a, show efficacy but face limitations due to receptor polymorphisms and off-target toxicity. Here, we report the development and characterization of a novel trispecific NK cell engager (TriKE) simultaneously targeting the activating receptor NKp30 and the tumor-associated antigen HER2, integrated with a modified interleukin-15 (IL-15 N72D) fused to the IL-15Rα sushi domain (IL-15RαSu) to enhance NK cell proliferation and persistence. Protein expression and affinity analyses confirmed the proper formation of the fusion protein with high-affinity binding to NKp30, HER2, and IL-15 receptor components. Flow cytometry demonstrated dose-dependent binding of the TriKE to primary human NK cells and HER2+ tumor cells. Functionally, the TriKE induced significantly greater NK cell activation, as measured by CD69 expression, compared with a bispecific engager lacking IL-15. Importantly, cytotoxicity assays revealed superior NK-mediated killing of HER2+ tumor cells upon prolonged exposure, highlighting the immunostimulatory effect of the IL-15 moiety. These results establish the αNKp30 TriKE as a potent platform to redirect NK cytotoxicity against HER2+ tumors, combining targeted receptor engagement with cytokine-driven activation to enhance NK cell-based cancer immunotherapy.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants and is a major health hazard for preterm infants worldwide. Hyperoxia-induced oxidative stress is one of the major risk factors for the development of BPD, and ideas for timely intervention in the development of BPD are urgently needed to understand this mechanism. The transmembrane protein TMEM106B is a key molecule in the regulation of autophagy function. However, its biological function in BPD remains elusive. In this study, we evaluated that TMEM106B expression was significantly elevated in BPD patients compared with healthy patients with an area under the receiver-operating characteristic curve of 0.7122, suggesting that TMEM106B expression may be associated with the development of BPD. We further found that TMEM106B expression levels were significantly elevated in the neonatal rat BPD model compared with healthy control rats. Hyperoxic stimulation promoted macrophage TMEM106B expression. Consistent with these findings, macrophage reactive oxygen species and apoptosis levels were decreased and autophagy was enhanced after TMEM106B silencing. Hyperoxic stimulation resulted in a significant decrease in TMEM106B expression after TLR3-JNK inhibition. Taken together, our results suggest that hyperoxia-induced oxidative stress inhibited macrophage autophagy by enhancing TMEM106B through the TLR3/JNK signaling pathway and elucidated its TMEM106B-ULK1-dependent mechanism. Therefore, our data support further investigation of TMEM106B as a key molecule interfering with BPD development.

Morphologic studies show increased mast cell activation during T-cell-mediated inflammation. Previous research demonstrated that microvesicles from activated T cells, but not from resting T cells, stimulate human mast cells via the MAPK pathway, leading to degranulation and cytokine release. This study investigates whether microvesicles derived from activated T cells also promote mast cell migration. Microvesicles were isolated from activated or resting T-cell supernatants, and mast cell migration was measured using a transwell assay. The molecular mechanisms were analyzed with specific inhibitors. Results showed that microvesicles derived from activated T cells significantly enhanced human mast cell chemotaxis, which depended on ERK and p38 phosphorylation but not on PI3 K. In addition, migration was mediated by the S1P1 receptor rather than S1P2 and by sphingosine kinase 1, indicating a role of S1P1 in mast cell migration induced by microvesicles derived from activated T cells. In summary, microvesicles derived from activated T cells act as chemoattractants, guiding mast cells to inflammatory sites where they become activated, highlighting their importance in T-cell-mediated inflammation.