Journal of Immunology Research最新文献

Background: Epilepsy is a common neurological disorder involving multiple genes and molecular pathways. Study of differentially expressed genes (DEGs) and hub genes related to epilepsy can help reveal the pathophysiologic basis and improve potential diagnostic and therapeutic strategies. Methods: Transcriptome data of two epilepsy datasets (GSE143272 and GSE32534) and single-cell sequencing data (GSE201048) were collected from the Gene Expression Omnibus (GEO) database. Differential expression analysis was performed using Limma R package, and the hub genes were identified and analyzed utilizing STRING database and Cytoscape software. The clusterProfiler R package was used to perform gene function enrichment analysis and an epilepsy diagnostic model was constructed with the hub genes. The model performance was assessed according to receiver operating characteristic (ROC) curves. Results: Multiple DEGs linked to epilepsy were identified and 20 common DEGs between the two datasets were revealed. Eleven hub genes closely associated with epilepsy were identified by protein-protein interaction (PPI) network analysis. CD3D, CD3G, CTSW, and JCHAIN were consistently expressed in the GSE143272 and GSE32534 datasets and all showed a low expression in epilepsy samples. In particular, the diagnostic model developed with the four genes demonstrated a strong discriminatory ability in both datasets (all area under curve (AUC) > 0.7). Functional enrichment and single-cell analysis revealed that these key genes were closely related to T cell function, suggesting that they may play an important role in the immune regulation of epilepsy. Conclusion: This study successfully identified four key genes linked to epilepsy, contributing to the molecular diagnosis of epilepsy.

Recombinant poxviruses have been extensively studied as vaccine vectors, yet the specific mechanisms by which they engage the immune system remain incompletely understood. ALVAC is a poxviral vector that was a component of the HIV vaccine used in the Thai RV144 trial, showing modest efficacy in reducing HIV acquisition. Here, we show that in vitro ALVAC-HIV infection of peripheral blood mononuclear cells (PBMCs) activates natural killer (NK) and mucosal-associated invariant T (MAIT) cells. This activation was partially dependent on monocytes, cGAS sensing, and production of IL-18 and type I IFN. Furthermore, ALVAC-HIV-mediated activation of NK and MAIT cells contributed to the activation of B cells. Modified vaccinia Ankara (MVA), another poxviral vector used for prevention of smallpox and mpox, similarly activated NK and MAIT cells. Overall, this suggests a conserved mechanism by which NK and MAIT cells could contribute to the immunogenicity of poxviral vectors.

Neutrophils are the first immune cells to be recruited to the site of infection and deregulated activation is linked to adverse outcome, especially in premature neonates. Dampening neutrophil activity may therefore be a means of preventing acute and chronic inflammatory diseases; however, little is known about potential drugs to modulate neutrophil activity. 4-Phenyl butyric acid (4-PBA) is a clinically used drug, which acts as a chemical chaperone to inhibit endoplasmic reticulum (ER) stress and to suppress immune activation. Here, we investigated the potential of 4-PBA to regulate neutrophil-mediated inflammation and specifically the recruitment cascade of neutrophils. We found that 4-PBA suppressed perinatal neutrophil recruitment cascade as assessed by fetal intravital microscopy (IVM), as well as transmigration of neutrophils through the endothelial compartment via the inositol-requiring enzyme (IRE)-1α/extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. Likewise, 4-PBA promoted an anti-inflammatory phenotype by suppressing the release of pro-inflammatory mediators in bone marrow neutrophils and endothelial cells in vitro. Taken together, our data indicate that 4-PBA can exert anti-inflammatory effects by limiting excessive neutrophil infiltration into inflamed tissues, thereby holding significant therapeutic potential in managing various inflammatory diseases.

Background and Objective: Melanoma is a complex malignancy where the interplay between immune cells, cytokines, and the tumor microenvironment (TME) significantly influences disease progression and patient outcomes. This review explores the involvement of the interleukin-2 (IL-2) cytokine family in both the development and therapeutic approaches for melanoma. Methods: A narrative literature review was conducted, synthesizing findings from studies on immune cell behavior, cytokine functions, and their implications in melanoma and other cancers. This narrative review emphasizes the roles of immune cells and cytokines in both promoting and inhibiting tumor growth. Results: Neutrophils, influenced by tumor-derived cytokines, can adopt phenotypes that either inhibit or promote tumor growth. B cells in the TME often correlate with better survival, although their regulatory forms can suppress immune responses. Tissue-resident memory T cells (TRM cells) are crucial for antitumor immunity, particularly in response to immune checkpoint inhibitors (ICIs). Dendritic cells (DCs) are vital for antigen presentation, yet their function can be compromised in melanoma. Macrophages frequently support tumor growth through immunosuppressive actions. The IL-2 cytokine family, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, plays diverse roles in immune regulation. These cytokines are involved in T-cell proliferation, B-cell differentiation, and modulation of other immune responses, influencing both tumor progression and the effectiveness of immunotherapies. Conclusions: Immune cells and cytokines are pivotal in the pathogenesis, progression, and immunotherapy of melanoma. Understanding their complex roles offers insights into potential therapeutic strategies, highlighting the importance of targeted immunotherapies in treating melanoma and possibly other cancers. Additional studies are required to clarify the precise mechanisms and interactions occurring within the TME to enhance treatment strategies.

Purpose: Characterization of immune system heterogeneity in COVID-19 patients by comparing the inflammatory markers heparin-binding protein (HBP), serum amyloid A protein (SAA), IL-6, and C-reactive protein (CRP) in relation to viral burden, immune response, and tissue damage. Also, determine if prolonged elevations in these markers are associated with long-term symptoms of COVID-19. Methods: This study enrolled 106 hospitalized patients with PCR-confirmed diagnoses of COVID-19. Blood samples were collected within 24 h of admission (t _24h), at 48 h (t _48h), 7 days (t _7d), and long-term, greater than 1 month, post discharge (t _LongTerm). Serum levels of HBP, SAA, IL-6, and CRP were measured using a commercial point-of-care device. Viral burden was assessed via serum viral spike S-protein serum levels and specific immunoglobulins G, M, and D against S&N proteins, and SARS-CoV-2 proteins were quantified. Tissue injury was evaluated by measuring HMGB-1 levels. Clinical data were reviewed retrospectively. Healthy individual samples served as controls. Results: COVID-19 patients exhibited significantly elevated serum HBP and SAA compared to healthy controls. SAA levels normalized over 1 month, whereas HBP, CRP, and IL-6 remained persistently elevated. Patients requiring intensive care unit (ICU) admission, endotracheal intubation, or extracorporeal membrane oxygen (ECMO) demonstrated higher CRP, IL-6, and HBP at initial assessment. However, after 48 h, only IL-6 was elevated in patients who subsequently expired. No significant correlations emerged between serum HBP levels and HMGB-1, viral spike protein levels, or antibodies against SARS-CoV-2 proteins. Pre-existing or acquired comorbidities did not significantly influence HBP or SAA concentrations. An analysis of biomarker profiles identified four distinct patient clusters, each characterized by unique inflammatory patterns that remained stable over time. Specifically, Cluster 1 exhibited low IL-6 with high SAA and CRP. Cluster 2 had low HBP with the highest IL-6. Cluster 3 demonstrated low SAA and CRP levels, and Cluster 4 exhibited robust inflammatory responses across all markers except IL-6. Conclusions: The persistence of inflammatory markers suggests ongoing inflammatory responses post-COVID-19 infection. Significant heterogeneity observed in inflammatory responses upon admission indicates multiple distinct inflammatory phenotypes, which may have implications for clinical outcomes and management strategies.

[This corrects the article DOI: 10.1155/jimr/3393342.].

Cancer cells promote the polarisation of tumour-associated macrophages (TAMs) into pro-tumorigenic M2-like phenotype, contributing to cancer progression. Reprogramming TAMs by viral immunotherapy vectors represents a promising strategy for cancer therapy. However, the factors driving macrophage reprogramming into a tumour-suppressing M1-like phenotype in response to viral vectors remain unclear. Alphaviral vectors, such as Semliki Forest virus (SFV), indirectly influence macrophages through cancer cell infection, cytokine gene delivery and tumour microenvironment (TME) modulation. This study examines macrophage transcriptomic alterations induced by SFV vectors. Murine mammary cancer cells were infected with SFV delivering tumour necrosis factor-α (TNFα) or interferon-γ (IFNγ) genes. Conditioned media from infected cells were used to treat bone marrow-derived macrophages (BMDMs) with subsequent analysis of the transcriptome. As a result, SFV-infected cancer cells significantly altered cytokine and chemokine profiles, reducing immunosuppressive factors (e.g., IL-10) and increasing inflammatory mediators (e.g., CXCL10 and CCL4). RNA sequencing revealed upregulation of genes associated with antigen presentation, interferon responses and M1 polarisation in macrophages treated with SFV/TNFα and SFV/IFNγ-conditioned media. SFV/IFNγ inhibited cancer-associated pathways (angiogenesis, glycolysis and extracellular matrix (ECM) remodelling) and enhanced cytotoxic lymphocyte (CTL) chemoattractants (CXCL9 and CXCL10). SFV/TNFα selectively upregulated Mmp2, Mmp14 and Ccl22. All SFV vectors upregulated PD-L1 (Cd274) expression. The study demonstrates that alphavirus-mediated gene delivery to cancer cells can impact macrophages, inducing proinflammatory responses and reprogramming them into anti-cancer phenotype. However, combining SFV/IFNγ with immune checkpoint inhibitors could potentially improve therapeutic efficacy by mitigating virus-induced suppressive signals in the TME.

Background: Acute lung injury (ALI) is the most common complication of sepsis. Despite considerable progress in the treatment of sepsis, the effective treatment strategies are lacking. A previous study has shown that imatinib reduces the rate of acute pulmonary damage in septic mice; however, the molecular mechanism remains unclear. Therefore, the current study aimed to investigate the potential mechanism by which imatinib alleviates ALI in septic mice. Methods: A septicemia model was established by intraperitoneal injection of lipopolysaccharide (LPS), followed by tail vein injection of imatinib in the treatment group. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory factors, and hematoxylin staining was used to detect pathological injury to the lung tissue. Tandem mass tag (TMT) quantitative labeling technology was used for proteomic sequencing analysis. The main target protein was identified through bioinformatics, and its expression was confirmed using western blotting. Results: We identified 128 differentially expressed proteins were associated with the protective effects of imatinib against septic lung injury. Functional enrichment analysis indicated that these proteins may be related to electron transfer, coagulation, and endothelial cell regulation in the oxidative respiratory chain. Enrichment of the nuclear factor-kappa B (NF-kB) signaling pathway, complement-coagulation cascade, and chemokine signaling pathway was also observed. Additionally, we found that the expression of CCAAT/enhancer-binding protein delta (CEBPD) and pyruvate dehydrogenase kinase 4 (PDK4) increased in the sepsis group but decreased in the imatinib group. Conclusion: Imatinib may reduce ALI in mice with sepsis by participating in oxidative respiratory and inflammatory responses, clotting response-related signaling pathways, and downregulating CEBPD and PDK4 expression.

Background: Harmine (HM) has several pharmacological effects; however, severe neurotoxicity limits its clinical application and development. HM neurotoxicity is associated with abnormal energy metabolism. This study aimed to explore the roles and underlying mechanisms of mitochondrial fusion and division in HM derivative H-2-168-induced neurotoxicity. Methods: PC12 cells were treated with H-2-168, Mdivi-1 (an inhibitor of mitochondrial division), or a combination of both. Cell viability, levels of reactive oxygen species (ROS), adenosine triphosphate (ATP), lactic dehydrogenase (LDH), mitochondrial morphology, and membrane potential were measured. Immunofluorescence (IF) and western blotting were used to determine the expression of apoptosis-, mitochondrial fusion-, and division-related proteins. Additionally, PC12 cells with Drp1 knockdown or Mfn2 overexpression were generated to explore their effects. Results: H-2-168 alone or in combination with Mdivi-1 significantly reduced PC12 cell viability, induced apoptosis, and impaired mitochondrial function. These effects were accompanied by increased levels of ROS and LDH, reduced ATP levels, upregulation of caspase-3, cytochrome c (Cyt-c), Drp1, and Fis1, and downregulation of Mfn2 and OPA1. Additionally, Drp1 knockdown or Mfn2 overexpression further enhanced the H-2-168-induced reduction in cell viability. Conclusions: These data implied that H-2-168 may initiate apoptosis in PC12 cells by influencing the balance between mitochondrial fusion and division, accompanied by changes in energy metabolism, which may induce neurotoxicity.

Vascular endothelial growth factor-A (VEGF-A) plays a pivotal role in inflammatory rheumatic diseases, including spondyloarthritis (SpA). Recently, we have demonstrated that the expression of VEGF-A in human classical monocytes is positively associated with the number of swollen and painful joints in SpA patients. Therefore, we tested whether the anti-VEGF-A therapy can affect the hallmarks of SpA in the SKG mouse model. When initiated at the disease onset, the administration of anti-VEGF-A monoclonal antibodies (mAbs) significantly reduced the objective symptoms of SpA in the curdlan suspension-treated mice compared to their untreated and isotypic control-treated counterparts. Micro-computed tomography (CT) imaging revealed substantial benefits of the treatment, with anti-VEGF-A mAbs-treated mice exhibiting preserved joint spaces, reduced number and depth of bone erosions, and limited new bone formation in hind paws, calcaneus, sacroiliac joints, and caudal vertebrae. These effects remained in contrast to the pronounced damage and osteogenesis in relevant skeletal regions of control animals. The histological assessment confirmed reduced synovial inflammation and bone erosions in anti-VEGF-A mAbs-treated mice, underscoring the efficacy of the treatment in mitigating SpA bone damage. Collectively, anti-VEGF-A mAbs treatment favors the maintenance of joint and spine structures, alleviates bone destruction and osteogenesis, and reduces local inflammation in the mouse SpA model. Our study pinpoints anti-VEGF-A mAb therapy as a promising avenue to understand the SpA pathogenesis and as a treatment option. It also addresses vascular and inflammatory aspects of the disease and illustrates the potential of the SKG mouse SpA model for assessing the long-term safety of anti-VEGF-A therapy before its clinical translation.