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Low-density neutrophils (LDNs) have been described in tumors and various autoimmune diseases, where they exhibit immune dysfunction and alter disease progression. Nevertheless, LDNs have been rarely reported in sepsis. We studied sepsis patients admitted to the intensive care unit. Wright-Giemsa stain assay and Transmission electron microscopy were performed to detect the morphology of neutrophils. Flow cytometry was used to analyze the number and function of LDNs. Concentration of cytokines was measured using ELISA. Neutrophil chemotaxis was examined using an under-agarose chemotaxis model. We found that LDNs were significantly elevated in patients with sepsis. Phenotypes and morphological characteristics suggest that LDNs may be formed by mixtures of neutrophils at various maturation stages. In vitro experiments showed that LDN formation was closely associated with neutrophil degranulation. We preliminarily discussed changes in immune function in LDNs. Compared with high-density neutrophils, expression levels of CXC chemokine receptor 4 on LDN surfaces were increased, phagocytotic capacity was decreased, and life span was prolonged. The chemotactic ability of LDNs was significantly reduced, possibly related to the increased expression of P2X1. These data suggest that LDNs are essential components of neutrophils in sepsis. To clarify the source and dysfunction mechanism of LDN in sepsis may be helpful for the diagnosis and treatment of sepsis in the future.

Background Although the immune function of neutrophils in sepsis has been well described, the heterogeneity of neutrophils remains unclear during the process of sepsis. Methods In this study, we used a mouse CLP model to simulate the clinical scenario of patients with sepsis, neutrophil infiltration, abnormal distribution and dysfunction was analyzed. LPS was used to stimulate neutrophils in vitro to simulate sepsis; single-cell gene sequencing technology was used to explore the immunological typing. To explore the immunological function of immunosuppressive neutrophils, PD-L1 knockout neutrophils were cocultured with lymphocytes from wild-type mice. Results We found that neutrophils presented variant dysfunction at the late stage of sepsis, including inhibition of apoptosis, seriously damaged chemotaxis and extensive infiltration into the tissues. Single-cell RNA sequencing revealed that multiple subclusters of neutrophils were differentiated after LPS stimulation. The two-dimensional spatial distribution analysis showed that Foxp3 + T cells were much closer to Ly-6G than the CD4 + and CD8 + cells, indicating that infiltrated neutrophils may play immunomodulatory effect on surrounding T-regs. Further observations showed that LPS mediates PD-L1 over expression through p38α-MSK1/-MK2 pathway in neutrophils. The subsets of highly expressed PD-L1 exert immunosuppressive effect under direct contact mode, including inhibition of T cell activation and induction of T cell apoptosis and trans-differentiation. Conclusions Taken together, our data identify a previously unknown immunosuppressive subset of neutrophils as inhibitory neutrophil in order to more accurately describe the phenotype and characteristics of these cells in sepsis.

Chronic diabetic wounds are primarily caused by infection, inflammation, and angiogenesis-related disorders. An ideal approach for treating chronic diabetic wounds is by combining anti-infection strategies, immune microenvironment regulation, and angiogenesis promotion. Vascular endothelial growth factor (VEGF) can promote the proliferation and migration of vascular endothelial cells, thereby promoting angiogenesis. However, the low stability and inability to target lesions limit its application. Polymorphonuclear neutrophil-derived exosomes (PMNExo) exhibit good delivery properties and can be used for the therapeutic delivery of VEGF. Furthermore, they retain the antibacterial ability of polymorphonuclear neutrophils (PMNs). Nonetheless, low PMNExo generation impedes its therapeutic applications. In this study, we prepared exosome mimetics (EM) from PMNs using the extrusion process; as a result, exosome yield significantly improved. To increase the residence of exosomes, an extracellular matrix (ECM) hydrogel, a thermosensitive material that can function as an in situ gel in vivo , was used as an exosome carrier. The active peptides in the ECM regulated the immune microenvironment of the wound. In summary, we loaded ECM with VEGF-encapsulated activated neutrophil exosome mimetics (aPMNEM) to develop VEGF–aPMNEM–ECM hybrid hydrogel for treating chronic wounds. The hydrogel accelerates the regeneration of chronic diabetic wounds. Our study provides a prospective therapy platform involving cytokines for treating different diseases. Graphical Abstract

The management of granulocytopenia-associated infections is challenging, and a high mortality rate is associated with traditional supportive therapies. Neutrophils—the primary defenders of the human immune system—have potent bactericidal capabilities. Here, we investigated the dynamic in vivo distribution of neutrophil transfusion and their impact on the treatment outcome of severe granulocytopenic infections. We transfused 89Zr-labeled neutrophils in the C57BL/6 mice and observed the dynamic neutrophil distribution in mice for 24 h using the micro-positron emission tomography (Micro-PET) technique. The labeled neutrophils were predominantly retained in the lungs and spleen up to 4 h after injection and then redistributed to other organs, such as the spleen, liver, and bone marrow. Neutrophil transfusion did not elicit marked inflammatory responses or organ damage in healthy host mice. Notably, allogeneic neutrophils showed rapid chemotaxis to the infected area of the host within 1 h. Tail vein infusion of approximately 107 neutrophils substantially bolstered host immunity, ameliorated the inflammatory state, and increased survival rates in neutrophil-depleted and infected mice. Overall, massive allogeneic neutrophil transfusion had a therapeutic effect in severe infections and can have extensive applications in the future.

As frontline cells, the precise recruitment of neutrophils is crucial for resolving inflammation and maintaining the homeostasis of the organism. Increasing evidence suggests the pivotal role of neutrophil chemotaxis in cancer progression and metastasis. Here, we collected clinical data and peripheral blood samples from patients with tumours to examine the alterations in the neutrophil quantity and chemotactic function using the Cell Chemotaxis Analysis Platform (CCAP). Transcriptome sequencing data of pan-cancer were obtained from The Cancer Genome Atlas (TCGA). Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, we selected a total of 29 genes from 155 neutrophil- and chemotaxis-related genes to construct the ChemoScore model. Meanwhile, nomogram-based comprehensive model was established for clinical application. Furthermore, immunofluorescence (IF) staining was employed to assess the relationship between the neutrophils infiltrating and the survival outcomes of tumours. In this observational study, the chemotactic function of neutrophils was notably diminished in patients. The establishment and validation of ChemoScore suggested neutrophil chemotaxis to be a risk factor in most tumours, whereby higher scores were associated with poorer survival outcomes and were correlated with various immune cells and malignant biological processes. Moreover, IF staining of tumour tissue substantiated the adverse correlation between neutrophil infiltration and the survival of patients with lung adenocarcinoma ( P  = 0.0002) and colon adenocarcinoma ( P  = 0.0472). Taken together, patients with tumours demonstrated a decrease in chemotactic function. ChemoScore potentially prognosticates the survival of patients with tumours. Neutrophil chemotaxis provides novel directions and theoretical foundations for anti-tumour treatment.

Hashimoto’s Thyroiditis (HT) is an autoimmune disorder characterized by metabolic disturbances. However, a comprehensive metabolic and lipid profile of HT has not been reported. The metabolic and lipid profile of HT can be comprehensively analyzed through metabolomics and lipidomics technologies, providing a detailed understanding of the disease’s biochemical alterations. Plasma samples were obtained from 20 mice, comprising 10 from the control group and 10 from the HT group. Plasma metabolomics and lipidomics were analyzed via LC-MS/MS. PCA, PLS-DA, and OPLS-DA of the preprocessed data matrix were conducted using the ropls package (V.1.6.2) in R. The identification of significant differential metabolites was based on the VIP scores in the OPLS-DA model and p-values (Student’s t-test). Metabolites (VIP exceeding 1 and p <  0.05) were classified as significantly different. Pathway annotation of these metabolites was carried out using the KEGG database to identify associated metabolic pathways. Pathway enrichment analysis was performed using the Python scipy. Stats package, with Fisher’s exact test employed to identify biological pathways most relevant to the experimental conditions. Metabolomics identified 6384 metabolites (2943 in positive ion mode and 3441 in negative), with 195 differential metabolites, comprising 114 upregulated and 81 downregulated in the HT group. Lipidomics analysis revealed 1054 lipid metabolites (695 detected in positive ion mode and 359 in negative), and 247 differentially expressed lipids were identified, including 165 upregulated and 82 downregulated in the HT group. KEGG enrichment analysis indicated that metabolites upregulated in the HT group were primarily associated with pathways such as Autophagy, Choline metabolism, PPAR signaling, and Glycerophospholipid metabolism. In contrast, pathways involved in Apoptosis, Cholesterol metabolism, Sphingolipid metabolism, EGFR tyrosine kinase inhibitor resistance, Th1 and Th2 cell differentiation, viral infection, and Chemokine signaling were suppressed. Metabolic and lipidomic dysregulation was observed in HT animal models, with pronounced alterations in Phospholipids, Eicosanoids, and Carnitines. Choline, Glycerophospholipid, and Linoleic acid metabolism pathways exhibited significant enrichment in HT.

Cadmium (Cd) is a pervasive environmental and industrial toxin that poses significant health risks. It readily moves through soil–plant systems, leading to global contamination and human exposure through diet, smoking, and pollution. The main purpose of this review is to explore the effect of Cd on physiological processes of different bodies’ organs, including the bones, kidneys, and liver, as well as the immune, cerebrovascular, cardiovascular, and reproductive systems. Accumulation of Cd in the body can result in poisoning with severe impacts on bone and kidney health, as well as reduced bone mineral density due to renal damage. Research has linked Cd to lung cancer and pulmonary toxicity, and elevated urinary biomarkers suggest compromised renal function. Cd also affects the cardiovascular, cerebrovascular, and immune systems; the liver; and reproductive systems, contributing to various diseases by disrupting blood pressure and calcium regulation, causing oxidative stress and DNA damage, and impairing cell functions. Ongoing research is essential to fully understand Cd-induced toxicological effects and to develop effective interventions to prevent exposure and mitigate health risks.

The pathophysiological mechanisms, especially the roles of immune cells, underlying early stages of severe burn injury have not yet been fully clarified. Here, we analyzed circulating neutrophils (PMNs) in healthy donors and early burned patients by single-cell RNA sequencing to provide a comprehensive transcriptional landscape of PMNs in heterogeneity and functional multiplicity. Circulating PMNs in the healthy donors and burned groups were divided into five subgroups (G3, G4, G5a, G5b, G5c) with different functions. The dominant subsets of PMNs in homeostasis and burn injury significantly differed between groups. In addition, cells in the same subpopulation had the same core identity markers but performed different functions in healthy and burned states. Under burned conditions, PMN activation was very evident and accompanied by clear degranulation and metabolic abnormalities. Interestingly, was found that PMN activation, degranulation, chemotaxis, phagocytosis and reactive oxygen species (ROS) production in burned patients significantly differed between day 1 and days 2 or 3, thus providing a theoretical basis for PMN interventions in early burn stages. Significantly, previously undescribed transcription factors were also identified, including ZNF-787, ZNF-467, ZNF-189, ZNF-770, ZNF-262. In conclusion, this study conducted for the first time a detailed analysis of the heterogeneity and functional multiplicity of PMNs in early stages of severe burn injuries. Our findings attempted to clarify the influence of PMN heterogeneity on the pathophysiology and related mechanisms of burn injuries, which can provide new ideas for further research in burn intervention.

BackgroundDespite many advances in treatment, the prognosis of patients with sepsis still remains poor. Polymorphonuclear leukocytes (PMNs) are the first line of defense against infection. This study aimed to reveal the reason and mechanism of the production of PD-L1+ PMNs in sepsis.MethodsCecal ligation and perforation mouse model was established to simulate sepsis. And PMNs were treated for 4 h, 12 h with or without 100 ng/mL (IFN-γ) for further gene sequencing. PD-L1, PD-1, Ly6G, and CD3 were detected by multiplexed immunofluorescence. In addition, expression of PD-L1 and function of PMNs were assessed by flow cytometry. Serum and cell culture supernatant were measured with ELISA assays. Western blot was used to verify the JAK2/STAT1 pathway.ResultsOur study demonstrates that PMNs are the main immune cells with high expression of PD-L1 during sepsis, and these cells, therefore, play a critical role in immunosuppression. In vivo studies demonstrated a specific interaction between PD-L1+ PMNs and PD-1+ T cells. In vitro studies further demonstrated that IFN-γ induced the production of PD-L1+ PMNs through the JAK2/STAT1 pathway. In addition, Fedratinib, an inhibitor of Jak2, was shown to significantly reduce the expression of PD-L1 in neutrophils.ConclusionsThese data demonstrate that secretion of IFN-γ by splenic T lymphocytes induces the production of PD-L1 + PMNs through the JAK2/STAT1 pathway in sepsis.

The function and heterogeneity of neutrophils in neonatal umbilical cord blood (UCB) have not been characterized. In this study, we analyzed the neutrophils in UCB and healthy adults using single-cell RNA sequencing analysis for the first time. We found that neutrophils divided into six subpopulations (G2, G3, G4, G5a, G5b, and G5c) with different marker genes and different functions under homeostasis. Compared with healthy adults, neutrophils of UCB were more naïve and have more obvious degranulation and activation functions. Moreover, we found significant differences in the amount and function of G5b cells between healthy adults and UCB. The amount of G5b group in UCB was lower, but it has more degranulation, secretion and activation functions. In addition, we noted a new subset of G5c labeled by CD52, which almost did not exist in UCB. Besides, its differential genes were enriched in terms such as protein synthesis and mRNA transcription. Furthermore, uncharacteristic transcription factors ZNF-276, ZNF-319 and ZNF-354A were identified in our study. In summary, we first examined the heterogeneity and functional diversity of neutrophils in UCB, and these data provided new insights into the mechanism of neutrophil-mediated diseases of neonates and the wider use of neutrophils in UCB.