Mediators of Inflammation最新文献

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited treatment options and frequent drug resistance. Novel therapeutic targets are urgently needed. We performed a druggable genome-wide Mendelian randomization (MR) analysis using blood cis-expression quantitative trait locus (eQTL) and HS genome-wide association study (GWAS) data. Colocalization, transcriptomic validation, single-cell RNA sequencing, and cell-cell communication analyses were integrated to explore gene function and cell-type specificity. We identified eight genes that showed significant associations with HS through MR analysis. Colocalization analysis further prioritized PSMA4 and MAST3 as the most promising druggable targets for HS. Specifically, PSMA4 (single nucleotide polymorphisms [SNPs] = 10; inverse-variance weighted [IVW] OR = 1.912, 95% CI: 1.492-2.450, p < 0.001; PP.H4 = 0.975) and MAST3 (SNPs = 15; IVW OR = 0.557, 95% CI: 0.453-0.686, p < 0.001; PP.H4 = 0.832) exhibited strong statistical associations. Transcriptomic validation revealed that PSMA4 was upregulated and MAST3 was downregulated in HS lesions. Further single-cell analysis revealed that PSMA4 was predominantly enriched in CD4⁺ T cells and involved in pro-inflammatory signaling, particularly the tumor necrosis factor (TNF) pathway. PSMA4 and MAST3 are potential therapeutic targets for HS. PSMA4 may promote inflammation via CD4⁺ T cell-mediated signaling, offering a novel avenue for treatment development.

[This corrects the article DOI: 10.1155/2022/6077570.].

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global epidemic, with growing evidence suggesting its adverse impact on brain function. However, the underlying mechanisms linking hepatic metabolic dysfunction to neurodegeneration remain unclear. In this study, we systematically investigated the liver-brain axis by integrating genetic epidemiology, experimental neuroscience, and transcriptomics techniques. Two-sample Mendelian randomization (MR) analysis revealed a potential causal relationship between MASLD and cognitive decline. These findings were validated in a high-fat diet (HFD)-induced MASLD mouse model, which exhibited hallmark features of metabolic dysfunction, including significant body fat accumulation and elevated serum levels of pro-inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α[TNF-α]). Behavioral assays demonstrated pronounced anxiety-like behaviors and impaired spatial memory. Neuropathological analysis revealed neuronal loss and structural alterations in the hippocampal dentate gyrus (DG), accompanied by astrocyte remodeling and M1 microglial polarization, indicating neuroinflammation-driven disruption of hippocampal circuits. At the molecular level, MASLD altered the expression of key hippocampal genes-including TCF7L2, LCN2, and AQP1-impacting immune response, lipid metabolism, and apoptotic pathways, which collectively contributed to cognitive deficits. Dual immunofluorescence staining, combined with Sholl and 3D analysis quantitatively characterized neuroglial morphological and functional changes, providing structural-level evidence for MASLD-related brain dysfunction. Taken together, our findings identify MASLD as a modifiable risk factor for neurodegeneration, with systemic inflammation playing a pivotal role in the liver-brain axis. This study highlights key genes and pathways underlying MASLD-induced cognitive impairment, advances understanding of metabolic-neural cross talk, and offers potential therapeutic targets for mitigating cognitive decline through intervention in the liver-brain axis, developing intervention strategies and highlight the therapeutic promise of targeting the liver-brain axis.

Background: Observational studies demonstrate that pro-inflammatory cytokines play a critical role in pericarditis. However, the causal association between circulating plasma proteins and pericarditis remains unestablished.

Objective: This research aimed to assess the causal association between plasma proteins and pericarditis and to investigate potential therapeutic targets.

Methods: A genome-wide association study (GWAS) involving 35,559 individuals of European ancestry was conducted using 4907 plasma proteins as instrumental variables (IVs). The causal relationship between plasma proteins and pericarditis was examined using inverse weighted median, variance weighting, and Mendelian randomization (MR)-Egger methods. Horizontal pleiotropy was evaluated via MR-Egger regression, and heterogeneity was quantified by Cochran's Q statistic. In addition, enrichment analyses, construction of a protein-protein interaction (PPI) network, and single-cell RNA sequencing (scRNA-seq) analysis were performed. Molecular docking was used to predict potential drug targets.

Results: MR analyses identified 67 plasma proteins with potential causal relationships with pericarditis, such as NEU1, GDNF, LAT, CASP8, ZFYVE27, and NAPA. Among them, elevated levels of NEU1, GDNF, and LAT increased the risk of pericarditis, whereas higher levels of CASP8, ZFYVE27, and NAPA decreased the risk of pericarditis. Pleiotropy tests and sensitivity analyses confirmed the stability of the findings. Moreover, scRNA-seq analysis revealed that genes such as extracellular matrix protein 1 (ECM1), CASP8, EPHA4, and CCL2 were specifically expressed in cardiac progenitor cells (CPCs). Molecular docking further identified compounds with anti-inflammatory, antioxidant, or immunomodulatory potential, including phorbol 12-myristate 13-acetate (PMA), cerivastatin, and melatonin.

Conclusion: This research examined the causal association between plasma proteins and pericarditis by MR analysis and identified several potential therapeutic targets. These findings provide theoretical evidence for targeted drug development and clinical prevention strategies for pericarditis.

Background: Gallstone disease is a condition affecting the digestive system, strongly linked to inflammation and lipid metabolism. Inflammatory markers derived from high-density lipoprotein (HDL), incorporating both immune cells and HDL-C, play a crucial role in assessing inflammatory responses. This study aims to explore the relationship between these HDL-related inflammatory indices and gallstone disease.

Methods: The study population was derived from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 and 2021-2023 datasets. To assess the association between HDL-related inflammatory indices and gallstone disease, weighted multivariable logistic regression and restricted cubic spline (RCS) analysis were utilized. Additionally, subgroup analysis was conducted to confirm the consistency of the results across different subpopulations.

Results: Among the 16,871 participants included in the study, 11.0% were diagnosed with gallstone disease. When compared to the lowest quartile, those in the highest quartile of lymphocyte-to-HDL cholesterol ratio (LHR), monocyte-to-HDL cholesterol ratio (MHR), neutrophil-to-HDL cholesterol ratio (NHR), and platelet-to-HDL cholesterol ratio (PHR) faced an elevated risk of gallstone disease by 58.6% (OR = 1.586, 95% CI: 1.143-2.2), 67.6% (OR = 1.676, 95% CI: 1.275-2.204), 68.7% (OR = 1.687, 95% CI: 1.244-2.287), and 42.7% (OR = 1.427, 95% CI: 1.101-1.849), respectively. The correlation between HDL-related inflammatory indices and gallstone disease was more pronounced in females, individuals without diabetes or hypertension, nonsmokers, and those who consumed alcohol.

Conclusions: This research identified a positive correlation between HDL-related inflammatory indices and gallstone disease in a nationally representative sample. These indices can be derived from routine blood tests at no additional cost, making them practical and cost-effective tools for early risk stratification and potential large-scale screening.

Background: Endometriosis (EM) is associated with immune dysregulation, while dysfunction of natural killer (NK) cells is regarded as a key mechanism underlying immune escape and the persistent growth of ectopic lesions.

Method: This study used single-cell RNA sequencing (scRNA-seq) on lesions from three patients with EM and on three normal endometrium samples and integrated these data with three bulk RNA-seq datasets from GEO (GSE105765, GSE7305, and GSE6364). Seurat, Monocle, limma, least absolute shrinkage and selection operator (LASSO), and support vector machine recursive feature elimination (SVM-RFE) were used for cell clustering, trajectory inference, differential expression analysis, and feature selection. Immune-cell composition and pathway activity were evaluated with CIBERSORT and GSVA. Gene expression was validated by qPCR, and cell migration and invasiveness were assessed using wound healing and Transwell assays.

Result: scRNA-seq resolved 11 clusters assigned to eight major cell types. By integrating pseudotime features with bulk data, 20 differentially expressed genes (DEGs) were prioritized, and machine-learning analyses identified three key genes: granulysin (GNLY), perforin 1 (PRF1), and ENTPD1. The three-gene model showed good discrimination in the training set and two external validation cohorts (AUCs 0.84, 0.67, and 0.77, respectively). GNLY and PRF1 were predominantly expressed in NK cells and CD8⁺ T cells and correlated with activation signatures, whereas ENTPD1 was highly expressed in endometrial stromal cells and enhanced their migratory and invasive capacities. ENTPD1 may contribute to disease via adenosine signaling-mediated modulation of NK-cell function. In silico analyses also nominated candidate agents targeting this pathway, including resveratrol, ibuprofen, and danazol.

Conclusion: This study highlights the central role of NK-cell dysfunction in EM pathogenesis and proposes GNLY, PRF1, and ENTPD1 as potential molecular diagnostic biomarkers. Notably, ENTPD1 appears to have dual functions, including immunomodulation and promotion of stromal cell migration, which promotes lesion formation. These findings provide a mechanistic rationale and actionable targets for earlier screening and targeted therapy in EM.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), and cancerous transformation of UC is closely associated with chronic inflammation of colonic tissues. Indigo naturalis (IN) prepared using a novel method (NIN) has exhibited beneficial efficacy against inflammatory and cancerous colonic cells. However, the underlying mechanism still remains to be elucidated. This study aimed to construct an inflammation model by the HT-29 colonic cancer cell line and to investigate the effect of NIN on an inflammatory cancer state and the possible mechanism. The results showed that NIN could reduce the increased expression of pro-inflammatory cytokine IL-1β in the inflammatory cancer cells and attenuate the inflammatory response; elevate the low expression of MUC2 in the inflammatory cancer state and restore the mucin secretion function; and inhibit the proliferation of HT-29 cells. Based on the activation of the aryl hydrocarbon receptor (AhR) signaling pathway, NIN increases the expression of the Wnt/β-catenin signaling pathway inhibitor Rnf43, inhibits the expression of nonphosphorylated β-catenin, and reduces the level of the pathway downstream target gene Axin2, which in turn inhibits the Wnt/β-catenin signaling pathway and inhibits the expression of Lgr5, a stem cell gene of colorectal cancer (CAC). The production of the above effects of NIN was blocked by the AhR antagonist CH223191. The in vitro studies verified that NIN alleviated UC by activing AhR signaling pathway, which in turn inhibited the Wnt/β-catenin signaling pathway. The possible mechanism of NIN on UC could be explained starting from the inflammation-cancer transformation. Furthermore, comprehensive research is expected between inflammation and cancer development.

The relationship between the C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index and disease activity of rheumatoid arthritis (RA) has not been explored at present. This study included 1058 RA patients and used a multiple linear regression model to evaluate the association between the CALLY index and 28 joint disease activity scores (DAS28) and further explored its potential nonlinear relationship using a two-stage segmented linear regression model. Multivariate adjusted analysis showed that CALLY was significantly negatively correlated with DAS28-erythrocyte sedimentation rate (ESR) (β = -0.119, 95% confidence interval [CI]: -0.145 to -0.093) and DAS28-CRP (β = -0.201, 95% CI: -0.226 to -0.177) (both p  < 0.001), and there was a dose-response relationship (trend p  < 0.001). Segmented regression analysis revealed a significant nonlinear correlation between the two, with inflection points of 0.499 and 0.555, respectively. Below the inflection point, CALLY has a significant negative impact on disease activity (DAS28-ESR: β = -2.102, 95% CI: -2.498 to -1.706); DAS28-CRP: β = -2.311, 95% CI: -2.591 to -2.031); after exceeding the inflection point, this negative correlation effect significantly weakens but still maintains statistical significance. The results of this study indicate a significant nonlinear relationship between the CALLY index and the DAS28 score, especially at low CALLY levels. This study suggests the potential of CALLY as a novel composite biomarker reflecting the inflammatory status and disease severity of RA.

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) regulate cell proliferation, differentiation, metabolic processes, and immune activities. Psoriasis is a systemic inflammatory disease with metabolic disorders as an important comorbidity in the pathogenesis of which members of the IGF family could also play a role. Therefore, we decided to evaluate the levels of members of the IGF signaling pathway in patients with psoriasis. Sixty-nine people were enrolled in our study: 34 patients with psoriasis and 35 controls. The following parameters were evaluated in serum obtained from peripheral blood: total cholesterol, triglycerides, high-density lipoprotein, fasting glucose, IGF-1, IGF-1R, IGF-2, IGF-2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP6, and insulin. The levels of several parameters differed between groups. The levels of fasting glucose, insulin, IGFBP3, and IGFBP6 were higher in patients with psoriasis, while the levels of IGF-1, IGF-1R, and IGBP4 were higher in controls. The results suggested that the IGF-1 signaling pathway can be involved in the pathogenesis of psoriasis and its comorbidities, especially metabolic disorders such as insulin resistance, diabetes, and metabolic syndrome. The novelty of our study is in its comprehensive assessment of the involvement of the IGF-1 signaling pathway in the pathogenesis of psoriasis and advances the understanding of the pathogenesis of psoriasis and its comorbidities.

Background: The immune system and inflammatory proteins influence hematologic malignancies, but causal links with immune cell phenotypes are unclear.

Methods: We applied a prespecified, multistage workflow: two-sample and multivariable Mendelian randomization (MVMR; 731 immune traits across 12 hematologic cancers), two-step mediation Mendelian randomization (MR) of 91 circulating inflammatory proteins, MAGMA/FUMA gene and pathway enrichment, and external validation with trait-specific genetic risk scores (GRSs) in UK Biobank (UKB). We then performed CCR2 perturbation assays in human monocytic leukemia cell line (THP-1) and immortalized bone marrow-derived macrophage (IBMDM) cells with artemin (ARTN) mRNA readouts and examined proteomic correlations for ARTN using the Olink inflammatory panel.

Results: Eight immune phenotypes showed FDR-significant causal associations with malignancy, seven of which remained independent in MVMR. In acute myeloid leukemia (AML), CCR2 on CD62L ⁺ myeloid dendritic cells (DCs) was associated with lower risk, whereas BAFF-R and CD19 on transitional B cells were associated with higher risk, CD19 on IgD^-CD38^dim B cells was associated with chronic myeloid leukemia (CML), and HLA-DR⁺ NK cells were protective in non-Hodgkin lymphoma (NHL). Mediation MR identified three protein mediators-CD40L, IL-33, and ARTN, with ARTN mediating the CCR2-AML association. GRS analyses reproduced risk directions, most prominently the protective CCR2-AML association. In THP-1 and IBMDM models, CCR2 inhibition or knockdown increased ARTN mRNA expression, functionally supporting a CCR2→ARTN regulatory relationship. Proteomic correlations positioned ARTN with immune-metabolic proteins (CLEC6A, SIGLEC6, NPC2, and MTHFD2). Pathway analyses highlighted membrane-proximal processes (external plasma membrane and IgG binding) and a 16p11.2 signal.

Conclusion: This integrative analysis identified CCR2-ARTN as a mechanistically supported immune-inflammation axis contributing to AML risk, offering a potential therapeutic target and warrants direct validation in primary CD62L ⁺ myeloid DCs.