Mediators of Inflammation最新文献

Background and aims: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with high heterogeneity and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis through dysregulated expression. We explored the effects and mechanisms of nuclear transcription factor NF-κB interacting lncRNA (NKILA) in ICC.

Methods: Bioinformatic analysis was performed to determine the expression and relationship of NKILA with metaxin 1 (MTX1), and translocase of outer mitochondrial membrane 40 (TOMM40) expression in ICC tissue samples. Cholangiocarcinoma cell lines were cultured in vitro and the transplanted tumor model was constructed in vivo to study the role of NKILA in ICC. Immunohistochemistry (IHC), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the effects of NKILA on the Warburg effect, autophagy, programed cell death 1 ligand 1 (PD-L1) expression, and CD8⁺ T cytotoxicity in ICC cells. RNA immunoprecipitation (IP) (RIP) assay and RNA-RNA pull down assays were utilized to detect the binding of NKILA and MTX1, and CO-IP was performed to assess the interaction between MTX1 and TOMM40.

Results: We found that NKILA, MTX1, and TOMM40 were substantially upregulated in ICC tissues, and NKILA silencing reduced MTX1-TOMM40 binding in ICC cells. NKILA facilitated proliferation, invasion, Warburg effects, and autophagy of ICC cells by regulating mammalian target of rapamycin (mTOR) pathway, PD-L1 expression, and CD8⁺ T cytotoxicity, while dichloroacetate (DCA) could reverse these effects. Mechanistically, NKILA binds directly to MTX1 mRNA, which stabilizes MTX1 mRNA and thereby promotes the expression of MTX1 protein. NKILA silencing could inactivate MTX1/TOMM40 axis to inhibit Warburg effect and autophagy-associated immune escape.

Conclusions: LncRNA NKILA promotes Warburg effect and immune escape in ICC by regulating the MTX1/TOMM40 axis.

Background: Vitiligo is a common depigmentary disorder characterized by progressive melanocyte (MEL) loss. While T-cell activation is central to its pathogenesis, the role of macrophages remains poorly understood. This study characterizes macrophage heterogeneity and function in vitiligo using single-cell transcriptomic analysis and experimental validation.

Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data from healthy and vitiligo-affected skin to identify macrophage subpopulations. Computational analyses included cell subpopulation clustering, pseudotime trajectory inference, cell-cell communication, and high-dimensional weighted gene coexpression network analysis (hdWGCNA). In vivo and in vitro experiments examined the effects of STAT1 suppression on the macrophage inflammatory phenotype and antigen presentation capacity.

Results: scRNA-seq analysis identified macrophages and T cell subsets enriched in vitiligo. Macrophage subclustering identified five subpopulations, with inflammatory antigen-presenting macrophages (Mac-InflamAP) significantly enriched in vitiligo lesions and M1-polarized. Pseudotime analysis revealed Mac-InflamAP as a terminal differentiation state. Cell-cell communication analysis showed Mac-InflamAP exerts TNF-mediated inhibitory effects on MELs while enhancing T-cell antigen presentation, thereby promoting MEL loss. hdWGCNA identified STAT1 as a key regulator highly expressed in Mac-InflamAP. In vivo, STAT1 inhibition by fludarabine ameliorated vitiligo progression by suppressing T cell activation and macrophage M1-polarization. In vitro experiments confirmed STAT1 suppression reduced macrophage M1 polarization, inflammatory phenotype, and antigen presentation capabilities.

Conclusions: This study reveals an uncharacterized inflammatory macrophage subpopulation crucial to vitiligo pathogenesis through dual mechanisms: direct MEL inhibition and enhanced T-cell activation. The identification of STAT1 as a key regulatory molecule provides a novel therapeutic target for vitiligo. These findings advance our understanding of immune-mediated mechanisms in vitiligo.

Background: Low-density lipoprotein (LDL) is a critical regulator of lipid metabolism and has been implicated in the development and progression of various malignancies. However, its specific roles and mechanisms in the ovarian cancer tumor microenvironment (TME) remain unclear. This study aimed to comprehensively elucidate the distribution, functional pathways, and prognostic value of LDL in ovarian cancer using single-cell transcriptome analysis.

Methods: Single-cell transcriptome data from ovarian cancer patients were analyzed. The AUCell algorithm was used to score LDL-related gene expression in different cell subsets, dividing cells into high and low LDL score groups. Functional pathway enrichment (Gene Set Variation Analysis [GSVA]) and cell-cell communication (CellChat) analyses were performed. Differentially expressed genes (DEGs) identified between the two groups were combined with bulk RNA-seq data from eight cohorts to construct the LDL-related ovarian cancer prognostic signature (LDLOCPS) using machine learning. Prognostic performance and immune landscape differences were evaluated between high and low LDLOCPS groups.

Results: LDL was predominantly highly expressed in myeloid cells (macrophages and monocytes) and stromal cells (fibroblasts, smooth muscle cells, and endothelial cells) within the ovarian cancer TME. GSVA revealed that the high LDL score group was significantly enriched for pathways including epithelial-mesenchymal transition (EMT), inflammatory response, coagulation, and angiogenesis. CellChat analysis demonstrated enhanced cell-cell communication involving IL6, CSF, and tenascin in the high LDL score group, with SPP1+ macrophages and monocytes showing stronger incoming and outgoing signals. The LDLOCPS model, constructed from bulk transcriptomic data and validated across eight cohorts, effectively stratified patients by risk; the high LDLOCPS group exhibited significantly worse overall survival. Receiver operating characteristic (ROC) and principal component analysis (PCA) analyses confirmed the robust predictive performance of LDLOCPS. Moreover, patients in the high LDLOCPS group showed reduced immune cell infiltration and lower expression of immune-related genes, suggesting an immunosuppressive microenvironment.

Conclusion: This study systematically reveals the spatial distribution of LDL within the ovarian cancer microenvironment and uncovers its regulatory roles in tumor progression through multiple signaling pathways. The LDLOCPS model provides a valuable tool for risk stratification and prognosis prediction in ovarian cancer. LDL-mediated microenvironmental and immunosuppressive effects may offer novel insights for developing targeted and immunomodulatory therapies in ovarian cancer.

[This retracts the article DOI: 10.1155/2016/4569521.].

[This retracts the article DOI: 10.1155/2022/6368311.].

[This corrects the article DOI: 10.1155/2023/8533476.].

Background: Efferocytosis, the phagocytic clearance of apoptotic cells, plays a key role in tumor progression and immune regulation, but its prognostic significance and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear.

Methods: Four efferocytosis-related pathways were curated, and the pathway activities were quantified in ccRCC. Prognostic genes were identified by univariate Cox regression and used to construct linear survival models with multiple algorithms, with the optimal model selected by cross-validation. Associations between the risk score and tumor mutational burden (TMB), mutation profiles, and copy number variation (CNV) were subsequently evaluated. Multiomics integration highlighted RAC1 as a key risk gene, which was further examined using single-cell and spatial transcriptomics (ST) to characterize expression patterns, tumor microenvironment interactions, and pathway enrichments. Protein-level validation was performed using immunohistochemistry (IHC) data from the Human Protein Atlas.

Results: Efferocytosis pathway activity was upregulated in ccRCC, increased with disease stage, and correlated with poorer survival. The ridge regression-based prognostic model demonstrated consistent predictive performance across independent datasets and was associated with higher TMB, specific mutation patterns, and increased CNV. Notably, RAC1, identified as the top weighted gene in the model, was overexpressed in association with copy number amplification, showing preferential enrichment in malignant core regions and strong links to oncogenic signaling.

Conclusion: Efferocytosis activation characterizes aggressive ccRCC. The developed prognostic model and identification of RAC1 as a central effector link efferocytosis-related risk to immune remodeling and oncogenic signaling, providing potential biomarkers and therapeutic targets.

Exercise is crucial for postmenopausal osteoporosis (PMOP) management, yet the comparative efficacy of different exercise modalities and the underlying mechanisms remain unclear. This study investigated the differential effects of distance-matched high-intensity interval training (HIIT) and moderate-intensity continuous exercise (MICE) on ovariectomy (OVX)-induced osteoporosis (OP) in mice. After 12 weeks of training, micro-CT analysis revealed that MICE, but not HIIT, significantly attenuated OVX-induced bone loss and microstructural deterioration. Crucially, only MICE suppressed osteoclastogenesis and reduced proinflammatory factors (interleukin [IL]-6, IL-1β, and tumor necrosis factor-alpha [TNF-α]) expression in the femur, serum, and colon. Mechanistically, MICE uniquely restored gut microbiota (GM) diversity, mitigated dysbiosis, and enhanced intestinal barrier integrity by upregulating the expression of tight junction proteins (TJPs; ZO-1, occludin, and claudin-1), thereby reducing systemic inflammation. In contrast, HIIT failed to ameliorate GM imbalance and intestinal permeability. Our findings demonstrate that the protective effect of MICE on OVX-induced OP is mediated through the gut-bone axis by modulating GM, repairing the intestinal barrier, and suppressing inflammatory osteoclast activation. This study provides novel evidence that the benefits of exercise on PMOP are modality-dependent, highlighting MICE as a superior strategy and offering mechanistic insights for optimizing exercise prescriptions.