Frontiers in Immunology最新文献

Background: Breast Cancer (BC) ranks among the top three most prevalent cancers globally and stands as the principal contributor to cancer-related fatalities among women. In spite of the substantial occurrence rate of BC, the early stage of this disease is generally regarded as curable. However, intra-tumor heterogeneity presents a formidable obstacle to the success of effective treatment.

Method: In this research, single cell RNA sequencing was utilized to dissect the tumor microenvironment within BC. Slingshot, CytoTRACE and Monocle 2 were applied to illustrate the differentiation process of each subpopulation in the pseudotime sequence. To comprehensively comprehend the tumor cells (TCs) in BC, an analysis of upstream transcription factors was carried out via pySCENIC, while downstream pathway enrichment was conducted through KEGG, GO and GSEA. The prognosis model was established based on the bulk data obtained from TCGA and GEO databases. Knock-down experiments were also implemented to explore the function of the transcription factor CEBPD in the TCs.

Results: Our in-depth analysis identified eight principal cell types. Notably, TCs were predominantly found within epithelial cells. The classification of TCs further uncovered five unique subpopulations, with one subpopulation characterized by high UGDH expression. This subpopulation was shown to possess distinct metabolic features in metabolism-related investigations. The intricate communication modalities among different cell types were effectively demonstrated by means of CellChat. Additionally, a crucial transcription factor, CEBPD, was identified, which demonstrated a pronounced propensity towards tumors and harbored potential tumor-advancing characteristics. Its role in promoting cancer was subsequently verified through in vitro knock-down experiments. Moreover, a prognostic model was also developed, and a risk score was established based on the genes incorporated in the model. Through comparing the prognoses of different UTRS levels, it was determined that the group with a high UTRS had a less favorable prognosis.

Conclusion: These outcomes contributed to the elucidation of the complex interrelationships within the BC tumor microenvironment. By specifically targeting certain subpopulations of TCs, novel treatment strategies could potentially be devised. This study shed light on the direction that future research in BC should take, furnishing valuable information that can be utilized to enhance treatment regimens.

Background: The tumor microenvironment plays a crucial role in the progression of both glioma and glioma-induced autoimmune encephalitis. However, there remains a significant lack of effective therapeutic targets for these diseases.

Method: We collected 54 CT images of glioma patients and 54 glioma-induced autoimmune encephalitis patients, respectively. Radiomics features were extracted from tumors and encephalitis regions using Python, followed by dimensionality reduction via random forest and lasso regression, and construction of radiomics-based risk scores. Genomic data matched with clinical information were analyzed to identify key prognostic genes significantly associated with risk scores. Gene expression was validated by immunohistochemistry using our clinical samples. Immune infiltration was evaluated using five algorithms (MCP-counter, EPIC, TIMER, QUANT and IPS). The association between hub genes and immune checkpoint markers as well as immunoregulation-related genes was also analyzed using Spearman correlation.

Results: We identified 980 radiomics features both in glioma and encephalitis patient images and selected four key features through lasso regression to build a radiomics-based risk score. COL22A1 was strongly correlated with the risk score and identified as the hub prognostic gene. COL22A1 expression was higher in glioblastoma tissues and cell lines, and correlated with clinical factors such as higher age, WHO grade, and IDH mutation status. Immune infiltration analysis indicated associations with diverse immune and stromal cell populations, including CD8⁺T cells, macrophages, and CAFs. COL22A1 was also positively correlated with immune checkpoints and immune-regulated genes.

Conclusion: Our study highlights the critical role of COL22A1 in gliomas and glioma-Induced Autoimmune Encephalitis, demonstrating its strong association with poor prognosis and its significant involvement in tumor immune regulation.

Tissue resident regulatory T cells (tissue Tregs) are vital for maintaining immune homeostasis and controlling inflammation. They aid in repairing damaged tissues and influencing the progression of fibrosis. However, despite extensive research on how tissue Tregs interact with immune and non-immune cells during tissue repair, their pro- and anti-fibrotic effects in chronic tissue injury remain unclear. Understanding how tissue Tregs interact with various cell types, as well as their roles in chronic injury and fibrosis, is crucial for uncovering the mechanisms behind these conditions. In this review, we describe the roles of tissue Tregs in repair and fibrosis across different tissues and explore potential strategies for regulating tissue homeostasis. These insights hold promise for providing new perspectives and approaches for the treatment of irreversible fibrotic diseases.

Introduction: Acute myocardial infarction (AMI) is a critical condition that can lead to ischemic cardiomyopathy (ICM), a subsequent heart failure state characterized by compromised cardiac function.

Methods: This study investigates the role of mitophagy in the transition from AMI to ICM. We analyzed AMI and ICM datasets from GEO, identifying mitophagy-related differentially expressed genes (MRDEGs) through databases like GeneCards and Molecular Signatures Database, followed by functional enrichment and Protein-Protein Interaction analyses. Logistic regression, Support Vector Machine, and LASSO (Least Absolute Shrinkage and Selection Operator) were employed to pinpoint key MRDEGs and develop diagnostic models, with risk stratification performed using LASSO scores. Subgroup analyses included functional enrichment and immune infiltration analysis, along with protein domain predictions and the integration of regulatory networks involving Transcription Factors, miRNAs, and RNA-Binding Proteins, leading to drug target identification.

Results: The TGFβ pathway showed significant differences between high- and low-risk groups in AMI and ICM. Notably, in the AMI low-risk group, MRDEGs correlated positively with activated CD4+ T cells and negatively with Type 17 T helper cells, while in the AMI high-risk group, RPS11 showed a positive correlation with natural killer cells. In ICM, MRPS5 demonstrated a negative correlation with activated CD4+ T cells in the low-risk group and with memory B cells, mast cells, and dendritic cells in the high-risk group. The diagnostic accuracy of RPS11 was validated with an area under the curve (AUC) of 0.794 across diverse experimental approaches including blood samples, animal models, and myocardial hypoxia/reoxygenation models.

Conclusions: This study underscores the critical role of mitophagy in the transition from AMI to ICM, highlighting RPS11 as a highly significant biomarker with promising diagnostic potential and therapeutic implications.

Single cell RNA sequencing (scRNA-seq) can be used to resolve the cellular and molecular heterogeneity within a tissue by identifying cell populations with an unprecedented granularity along with their transcriptional signatures. Yet, the single cell gene expression profiles of cell populations in the healthy canine lung tissue remain unexplored and such analysis could reveal novel cell populations or markers lacking in dogs and facilitate comparisons with lung diseases. Using fresh healthy lung biopsies from four dogs, we conducted droplet-based scRNA-seq on 26,278 cells. We characterized 46 transcriptionally distinct cell subpopulations across all lung tissue compartments including 23 immune, 13 mesenchymal, five epithelial and five endothelial cell subpopulations. Of note, we captured rare cells such as unconventional T cells or Schwann cells. Differential gene expression profiles identified specific markers across all cell subpopulations. Fibroblasts clusters exhibited a marked transcriptional heterogeneity, some of which might exert immune regulatory functions. Finally, the integration of canine lung cells with an annotated human lung atlas highlighted many similarities in gene expression profiles between species. This study thus provides an extensive molecular cell atlas of the healthy canine lung, expanding our knowledge of lung cell diversity in dogs, and providing the molecular foundation for investigating lung cell identities and functions in canine lung diseases. Besides, the occurrence of spontaneous lung diseases in pet dogs, with phenotypes closely resembling those in humans, may provide a relevant model for advancing research into human lung diseases.

[This retracts the article DOI: 10.3389/fimmu.2018.01666.].

[This corrects the article DOI: 10.3389/fimmu.2022.1066268.].

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial. Among various factors, lipopolysaccharides (LPSs) from Gram-negative bacteria, such as E. coli, are considered potential causative agents. Despite significant advancements in the field, there is still no cure. In this study, we investigated the neuroprotective effects of ambroxol against LPS-induced neuroinflammation, oxidative stress, neurodegeneration, and the associated cognitive dysfunction. Intraperitoneal injection of LPS (250 µg/kg every alternative day for a total of seven doses over 14 days) triggered glial cell activation, neuroinflammation, oxidative stress, and neurodegeneration in the mouse brain. Ambroxol treatment (30 mg/kg/day for 14 days) significantly reduced neuroinflammation and oxidative stress compared to LPS-treated mice. Immunoblotting and immunofluorescence results showed that ambroxol reduced levels of Toll-like receptor 4 (TLR4) and oxidative stress kinase phospho-c-Jun N-terminal Kinase 1 (p-JNK). It also decreased astrocyte and microglia activation in the cortex and hippocampus of LPS+ Amb-treated mice, as indicated by the downregulation of GFAP and Iba-1. Furthermore, ambroxol-reversed LPS-induced neuroinflammation by inhibiting inflammatory mediators, such as IL-1β and TNF-α, through regulation of the transcription factor p-NFkB. Persistent neuroinflammation disrupted the natural antioxidant mechanisms, leading to oxidative stress. Ambroxol treatment upregulated antioxidant markers, including Nrf-2, HO-1, and SOD, which were downregulated in the LPS-treated group. Additionally, ambroxol-inhibited lipid peroxidation, maintaining malondialdehyde levels in the mouse brain. Ambroxol also improves synaptic integrity by upregulating synaptic biomarkers, including PSD-95 and SNAP-23. Overall, ambroxol demonstrated anti-inflammatory, antioxidant, and neuroprotective effects in LPS-treated mice, highlighting its potential benefits in neurological disorders.

Recent studies on the pathogenesis of leukemia have led to remarkable advances in disease treatment. Numerous studies have shown the potential and viability of immune responses against leukemia. In the classical pathway, this process is often initiated by the upstream activity of CD39, which hydrolyzes extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to AMP. Subsequently, CD73 acts on AMP to generate adenosine, contributing to an immunosuppressive microenvironment. However, CD73 can also utilize substrates derived from other molecules through the non-canonical NAD⁺ pathway, specifically via the CD38/CD203a/CD73 axis, further enhancing adenosine production and facilitating immune escape. Targeting CD73 has shown potential in disrupting these immunosuppressive pathways, thereby enhancing anti-leukemic immune responses and improving patient outcomes. Inhibiting CD73 not only reduces the levels of immunosuppressive adenosine but also increases the efficacy of existing immunotherapies, such as PD-1/PD-L1 inhibitors, making it a versatile therapeutic target in leukemia treatment. This review discusses the potential of CD73 as a therapeutic target and emphasizes its unique position in the immune escape mechanism of leukemia. Moreover, this review provides an overview of the current research progress and future trends, emphasizing the clinical significance of targeting CD73 and other potential therapeutic strategies in leukemia.