Mediators of Inflammation最新文献

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.

A series of intestine-related alterations have been considered a key factor in triggering sepsis, with increased apoptosis of intestinal epithelial cells (IECs) notably contributing to this process. Compromised gut barrier due to IEC apoptosis promotes bacterial translocation and inflammatory responses, which in turn escalates to further IEC death and barrier defects. Nevertheless, the precise mechanisms that safeguard IECs from apoptosis and interrupt this vicious cycle are yet to be elucidated. Here, we report that Grb2-associated binder 1 (Gab1) expression is diminished in the intestines of both septic patients and established sepsis models. Epithelial Gab1 deficiency rendered mice susceptible to lipopolysaccharide (LPS)-induced sepsis by sensitizing IECs to apoptosis, thereby contributing to systemic inflammation and markedly exacerbating septic lethality. Mechanistically, Gab1 mitigated apoptotic signaling via IKKβ-dependent NF-κB activation and subsequent transcriptional regulation of apoptotic genes in response to TNF-α. Collectively, our findings define a protective role for Gab1 in sepsis-induced intestinal injury by sustaining apoptotic balance and intestinal homeostasis, which provides new insights into therapeutic strategies for sepsis management, particularly those aiming at restoring immune homeostasis and improving barrier function.

Purpose: Allergic conjunctivitis (AC) is a condition with a rising prevalence that occasionally leads to irreversible visual impairment. However, few novel therapeutic targets have been identified for AC. The investigation aims to utilize the Mendelian randomization (MR) technique to explore the causal impacts exerted by the plasma proteome on AC.

Methods: An evaluation was conducted on a two-sample MR study utilizing 2,940 plasma proteins from the UK Biobank Pharma Proteomics Project (UKB-PPP) to investigate their causal links with AC. Confirmation of these MR results was achieved using Summary-data-based MR (SMR) and Bayesian colocalization techniques. Moreover, evaluations concerning the druggability of proteins, interactions among proteins, and phenome-wide MR (Phe-MR) studies were conducted to ascertain the functionalities of the identified proteins implicated in causality.

Results: MR analysis identified five circulating proteins (TLR1, ING1, RALY, CSF2, and ITGAM) whose genetically predicted plasma levels were significantly associated with AC risk (P _FDR < 0.05). Functional enrichment analysis of the identified proteins revealed statistically significant biologically relevant pathways, including macrophage activation and pathways of plasma membrane signaling receptor complex, suggesting underlying immune and receptor-mediated mechanisms in AC. SMR and HEIDI validation supports four (TLR1, ING1, ITGAM, and CSF2) of five MR-identified proteins as causal candidates for AC. Subsequent colocalization analysis provided further support for two credible proteins (ING1 and CSF2). Protein druggability suggests CSF2 and ING1 as novel and potentially druggable candidates for AC.

Conclusions: Our research identified proteins that appear to have causal effects and could serve as potential therapeutic targets for AC.

Objective: To analyze the direct and indirect associations between structural, functional, and systemic variables in patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and controls using structural equation modeling (SEM).

Methods: A cross-sectional observational study was conducted including 156 participants: 55 with POAG, 49 with NTG, and 52 age- and sex-matched controls. Clinical variables included intraocular pressure (IOP), central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR), and visual-field mean deviation (MD). Systemic variables comprised age and cardiovascular risk factors (hypertension, diabetes, and dyslipidemia). SEM was applied to assess direct and indirect effects on the diagnosis of glaucoma.

Results: The model showed a good overall fit (χ ²(9) = 15.968; p = 0.068; χ ²/df = 1.774; CFI = 0.972; RMSEA = 0.071) and explained 46.0% of the variance in glaucoma diagnosis (R ² = 0.460). The most influential predictors were VCDR (β = 0.40), age (β = 0.14), and cardiovascular risk factors (β = 0.19). A significant negative correlation was observed between CCT and MD (r = -0.29), indicating greater functional damage in eyes with thinner corneas. An inverse association between cardiovascular risk burden and IOP was also identified (r = -0.18).

Conclusions: Our findings support the hypothesis of distinct glaucomatous phenotypes, including a vascular subtype with lower IOP and altered perfusion, potentially influenced by systemic comorbidities and chronic treatments. Reduced CCT was also confirmed as an independent marker of advanced functional loss. SEM helps disentangle complex mechanisms and may inform personalized therapeutic strategies, particularly in NTG.

Characterized by its capacity to induce organ failure, sepsis constitutes a life-threatening pathological state with high incidence and mortality rates. Current treatments primarily focus on antimicrobial therapy and organ support, lacking direct interventions targeting the restoration of cellular or organelle function. Among these mechanisms, mitochondrial dysfunction and overactivation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome stand out as key pathological hallmarks. As a classic inflammasome, the NLRP3 inflammasome, upon activation, drives cellular pyroptosis and massive release of inflammatory mediators. Beyond their role as cellular energy generators, mitochondria participate in the modulation of inflammatory responses and oxidative stress control. Mitochondrial quality control (MQC) serves as a prerequisite for the orderly performance of mitochondrial physiological functions. Disruption of MQC invariably results in mitochondrial dysfunction, triggering liberation of mitochondrial reactive oxygen species (mtROS) along with mitochondrial damage-associated molecular patterns (mtDAMPs), which serve as direct triggers for NLRP3 inflammasome formation and stimulation. This process disrupts MQC, exacerbates mitochondrial dysfunction, and forms a mutually reinforcing "MQC imbalance-NLRP3 overactivation" vicious cycle that drives disease progression. This review aims to: (1) systematically elucidate the complex bidirectional regulatory mechanisms between the NLRP3 inflammasome and MQC in the context of sepsis, (2) summarize the latest research progress on targeted intervention strategies based on this vicious cycle, and (3) discuss the challenges in clinical translation and future directions of these strategies.