Immunology最新文献

Radiation-induced jaw injury is a serious and debilitating complication following head and neck radiotherapy (RT). The irradiation process triggers the recruitment and maladaptive activation of immune cells, thereby disrupting the delicate homeostasis of the jawbone. Despite its clinical significance, a comprehensive understanding of the osteoimmune microenvironment involved in underlying radiation-induced jaw injury remains incompletely understood. In this study, we comprehensively profiled the transcriptional landscape of mandibular bone marrow at single-cell resolution using single-cell RNA sequencing (scRNA-seq). Our analysis revealed a marked infiltration of conventional dendritic cells (cDCs). A specific subcluster of migratory dendritic cells (migDCs) characterised by the expression of genes related to maturation, migration and immune regulation was annotated. Following RT, these migDCs migrated to the draining lymph nodes. However, reduced secretion of neutrophil-derived secreted phosphoprotein 1 (SPP1) was found to impair migDC development through the SPP1/CD44/NF-κB signalling pathway, leading to an immature cDC phenotype. We also observed weakened intercellular interactions between cDCs and T cells, contributing to an imbalanced and immunosuppressive osteoimmune microenvironment after radiation exposure. Overall, our study highlights the critical role of decreased SPP1 in modulating migDC function and its subsequent impact on jawbone immune dynamics following RT.

Obesity is a chronic disease associated with systemic inflammation caused by excess visceral fat and pro-inflammatory cytokines such as IL-1β and IL-6. Inflammasomes-particularly those involving genes such as NLRP1, AIM2 and MEFV-play a key role in this process. High-intensity interval training (HIIT) can counteract this inflammation; however, it remains unclear how HIIT modulates inflammasome gene expression in obesity. This study investigated whether HIIT can alter the expression of genes related to the inflammasomes NLRP1, AIM2 and MEFV in obese individuals. The results showed that, after 8 weeks of HIIT, there was an increase in the expression of the genes AIM2, MEFV, CARD16 and CARD18. The increase in CARD16, known to inhibit caspase-1 dimerisation, reinforces the hypothesis related to decreased inflammation, evidenced by the absence of clear activation of the NLRP1 inflammasome and by lower serum IL-1β concentrations in trained participants. Although CARD18 was also upregulated, its function remains ambiguous, and it may act as an inhibitor or modulator of inflammation. Therefore, we conclude that HIIT is a promising intervention for modulating inflammatory genes in individuals with obesity, with the potential to reduce systemic inflammation and its pathological effects.

Mucosal-Associated Invariant T (MAIT) cells are a subset of T cells with potential for rapid cytotoxic and inflammatory functions. Dysregulation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway, particularly involving STAT1 and STAT3, has been implicated in MAIT cell dysfunction in certain diseases. However, the transcriptional mechanisms regulating their effector functions, particularly the role of various STAT proteins, remain poorly understood. Using RNA sequencing and proteomics data, and experimental validation through in vitro assays using MAIT-specific stimulation and small molecule inhibitors, we analysed the impact of STAT1, STAT3 and STAT5 on MAIT cell activation and function. Flow cytometric analysis was used to assess the functional implications of manipulating STAT proteins and the metabolic regulator HIF1α in MAIT cells. Our findings show that enhanced STAT1 activity negatively impacts MAIT cell effector functions, including granzyme B and interferon-γ expression, while STAT3 and STAT5 are essential for promoting MAIT cell activation, function and glycolytic responses. Additionally, we identify HIF1α as a key regulator of these processes, suggesting that metabolic reprogramming plays a critical role in MAIT cell activation and function. This study highlights the critical roles of STAT1, STAT3, STAT5 and HIF1α in regulating MAIT cell effector functions, expanding our understanding of the molecular mechanisms underlying MAIT cell dysfunction. Our work lays the foundation for future research and applications aimed at modulating MAIT cell activity in immune-related diseases and malignancies.

Glioblastoma (GBM) remains highly lethal due to intrinsic and extrinsic mechanisms, of which the immunosuppressive tumour microenvironment (TME) collectively limits treatment efficacy. This review synthesises recent advances in understanding how metabolic reprogramming, epigenetic remodelling and immune cell dysfunction converge to establish a stable immunosuppressive network dominated by tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells and exhausted T cells. We further summarise emerging therapeutic strategies, including myeloid-targeting agents, epigenetic modulators, metabolic inhibitors and combination immunotherapy, and discuss their clinical potential in overcoming GBM immune resistance. These insights provide a mechanistic and translational framework for developing next-generation multimodal treatment approaches.

Lactate metabolism plays a crucial role in immune cell function, particularly during inflammation or metabolic stress. Under these conditions, immune cells often undergo a metabolic shift towards glycolysis, resulting in increased lactate production. This reprogramming not only provides energy but also influences cellular signalling pathways that regulate gene expression and immune responses. A key outcome of elevated lactate levels is lactylation, a novel post-translational modification where lactate molecules are covalently attached to proteins, typically at lysine residues. Lactylation regulates protein activity and function, impacting transcription factors, enzymes and other proteins involved in immune cell activation, differentiation and inflammation. The process of lactylation is controlled by specific enzymes known as 'writers', 'erasers' and 'readers', which add, remove and recognise lactate modifications on proteins. Lactylation plays a significant role in immune cell function, influencing cytokine production, immune cell proliferation and the regulation of inflammation. Abnormal lactylation can contribute to the pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), by enhancing immune cell activation and promoting chronic inflammation. Elevated lactate levels in these diseases exacerbate immune responses, leading to tissue damage and autoantibody production. Targeting lactate metabolism or modulating lactylation presents a promising therapeutic strategy for autoimmune diseases. By regulating the enzymes involved in lactylation or controlling lactate accumulation, it may be possible to modulate immune responses, reduce inflammation and alleviate disease symptoms. Although current evidence largely derives from pre-clinical models and cell-based studies, emerging findings suggest that targeting lactate metabolism or modulating lactylation represents a promising therapeutic approach for autoimmune diseases. Future clinical studies are warranted to validate the translational potential of lactylation-related pathways and to develop safe and effective therapeutic strategies.

Neutrophils are the most abundant type of leukocyte found in human peripheral blood, with approximately 1 × 10¹¹ produced daily in the bone marrow. They play a crucial role as the first line of defence against microbial infections. Neutrophils utilise various mechanisms to combat pathogens, including phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs). Upon exposure to bacteria, neutrophils may release some of their mitochondria into the extracellular environment, which then tag bacteria. This process aids in the phagocytosis of the bacteria, enhancing their elimination within the neutrophil's phagolysosomes. According to the endosymbiotic theory, mitochondria originated from an alpha-proteobacterium. Since many bacteria possess antimicrobial mechanisms that enable them to survive in resource-limited ecosystems, we inquired whether mitochondria might have retained or developed direct bacteriostatic/bactericidal capabilities. Mitochondria were extracted from neutrophils, and Staphylococcus aureus was selected as the bacterial target. Bacterial growth was assessed using Colony Forming Units (CFU) counts and turbidimetry (optical density) in cultures containing only bacteria or bacteria combined with extracellular mitochondria; bacterial LIVE/DEAD assays were also performed. The interaction between mitochondria and bacteria was analysed using scanning and transmission electron microscopy. The results demonstrated that the presence of mitochondria reduced bacterial growth in culture; however, LIVE/DEAD assays showed that most bacteria remain viable. Together, these findings suggest that extracellular mitochondria mostly induce a viable but non-culturable (VBNC) state in S. aureus. The interaction between mitochondria and bacteria was strong, leading to morphological changes in the bacteria and, in some instances, this interaction ultimately caused the disruption of the bacterial cell wall and the loss of intracellular contents. Morphological changes were also observed in the mitochondria, including the formation of vesicular structures. Exposure of the mitochondria to MitoQ, a potent mitochondrial reactive oxygen species (mROS) inhibitor, partially reversed its effect on S. aureus CFU counts but had no effect on viability or the interaction between mitochondria and bacteria. Our findings suggest that cell-free extracellular mitochondria possess the potential for direct bacteriostatic and, to a lesser extent, bactericidal activity, which is at least partially mediated by mROS.

Ficolin-1 (FCN1, M-FCN), the key pattern recognition molecule of the innate immune system, possesses a collagen-like domain and a fibrinogen-like domain, exhibiting bidirectional immunomodulatory functions that influence immune homeostasis and disease progression. Recent studies reveal that beyond its well-established roles in pathogen recognition and complement activation, FCN1 orchestrates the balance between pro-inflammatory and anti-inflammatory responses, facilitating crosstalk between innate and adaptive immunity. This review synthesises cutting-edge research to systematically elucidate the multifaceted roles of FCN1 in human diseases, including autoimmune disorders, infectious diseases, tumour, cardiovascular and cerebrovascular disease. We highlight how FCN1 exerts its regulatory effects through diverse mechanisms ranging from pathogen binding and clearance to cytokine secretion modulation and immune cell fate determination, ultimately shaping disease susceptibility, progression and prognosis. By compiling these groundbreaking findings, we propose FCN1 as a pivotal orchestrator of immune responses, providing a theoretical foundation for its translation into diagnostic biomarkers and novel therapeutic targets in precision medicine. This review advocates for the establishment of standardised FCN1 assays and large-scale clinical validation to accelerate its transformation from bench to bedside.

During tuberculosis (TB), organ-specific immune responses and intracellular pathways play critical roles in disease progression and prognosis. Identifying genes that regulate these immune mechanisms remains a key challenge in improving TB management strategies. To investigate genes potentially associated with enhanced resistance to TB and the modulation of immune responses, we analysed RNA-seq data from whole cells isolated from the lungs and livers of mice infected with Mycobacterium tuberculosis (Mtb) at two time points that represent different outcomes. We hypothesised that these two organs mount distinct responses to infection, supported by differences in the immune response and bacterial burden kinetics observed in each tissue. Our analysis revealed differential gene expression profiles between the lungs and livers, primarily involving metabolic and immune-related pathways. Through meta-analysis, we identified orthologous genes shared between Mtb-infected mice and human patients with latent pulmonary TB. In the omics analysis, the four genes, Creb3l1, Myo7b, Cyyr1, and Cbs, were differentially expressed and associated with either resistance or susceptibility. In vitro assays further demonstrated that knockdown of CREB3L1 in Mtb-infected THP-1 or primary human monocytes impaired key effector functions, including phagocytosis, bacterial killing, and apoptosis. Taken together, these findings indicate that CREB3L1 possibly contributes to the regulation of genes essential for bacterial control in the lungs during latent TB infection. In contrast, its increased expression in the peripheral blood of patients with severe TB is more likely linked to systemic inflammatory dysregulation rather than direct antimicrobial activity. Notably, CREB3L1 expression in these patients positively correlated with cytokines such as IL-17, IL-12, and IFN-γ, which are central to macrophage activation and effector T cell recruitment. Thus, CREB3L1 appears to play a dual role in TB: under controlled infection, it acts as an immunomodulator limiting excessive pulmonary inflammation, while in severe disease, it may reflect an attempt by the host to amplify inflammatory responses to counteract progressive infection.

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene, resulting in abnormal haemoglobin S (HbS). Beyond genetic mutation, dysregulation of immune-related genes such as those regulating NF-κB signalling, inflammasome activation and type I interferon responses exacerbates the inflammatory milieu and drives many of the complications observed in SCD. Chronic inflammation, linked to disease severity, highlights the crucial role of the immune system in SCD pathophysiology. Immune dysregulation in SCD leads to chronic inflammation, heightened infection risk and possible autoimmune reactions. Immune dysregulation is driven by splenic damage and pro-inflammatory cytokines from sickled red blood cells. While progress has been made studying innate immune cell roles, the adaptive immune system's contributions remain poorly understood. T-cell abnormalities in SCD highlight the complexity of adaptive immune responses. Alterations in T-cell counts, shifts in Th1/Th2 responses and changes in regulatory T-cell behaviour reflect immune dysregulation, further contributing to chronic inflammation and disease progression. While studies have focused on polyclonal T-cell phenotyping, antigen-specific T-cells, crucial for immune activation, remain underexplored. Focusing on antigen-specific T-cell responses will deepen our understanding of adaptive immune dysfunction in SCD and aid in developing targeted therapies to manage the disease. Furthermore, there is significant impairment in the B cell compartment in SCD, including reduced B cell proliferation, fewer memory B cells and abnormalities in class-switching memory B cells. These defects weaken antigen-specific immune responses, mainly by lowering IgM-secreting memory B cells, essential for early defence against infections. The loss of these cells also diminishes vaccine effectiveness, leaving patients more vulnerable to infections. Additionally, impaired memory B cell differentiation and class switching contribute to an increased risk of infections and autoimmune complications, highlighting the need for targeted immune therapies in the management of SCD. This review highlights the need to explore dysregulation in innate and adaptive immune mechanisms in SCD. Investigating T and B cell dysfunctions, especially antigen-specific immune activation, is crucial for developing immune-targeted therapies and improving vaccine responses, ultimately advancing treatments and enhancing the quality of life and survival for SCD patients.

Dendritic cells (DCs) play a central role in both the development and maintenance of adaptive immunity by their ability to prime and regulate T cell function. These interactions between DCs and T cells are crucial to the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid differentiation primary response protein 88 (MyD88) signalling is pivotal in the pathogenesis of MS and EAE; however, its specific contributions across various cell types in the context of these conditions remain inadequately understood. In this study, we reanalysed single-cell RNA sequencing data from MS patients and revealed significant upregulation of MYD88 in DCs and CD4⁺ T cells isolated from PBMCs of MS patients. Single-cell RNA sequencing analysis revealed that during the peak phase of EAE, Myd88 is highly expressed in moDCs and pDCs compared to cDCs. Notably, the absence of Myd88 in DCs resulted in significantly reduced interactions with T cell clusters. Our in vivo and in vitro results showed that while MyD88 deficiency did not affect lymphocyte production in the thymus, it resulted in impaired Th1 and Th17 cell differentiation and diminished T cell activation. Mechanistically, MyD88^-/- DCs exhibited impaired maturation and a reduced production of pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-12, which may be linked to their role in directing Th1 and Th17 cell differentiation. Our findings suggest that MyD88 is essential for the priming of inflammatory T cells and the activation of DCs, and their interactions with T cells, underscoring its role in neuroinflammation. This study highlights the potential therapeutic implications of targeting MyD88 pathways in MS and related disorders.