Journal of Inflammation Research最新文献

Background: Ocular graft-versus-host disease (oGVHD) often presents with subtle and nonspecific symptoms following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Current diagnostic methods primarily depend on subjective clinical evaluations with limited sensitivity. This study aimed to identify serum pyroptosis-related cytokines associated with oGVHD and to develop a cytokine-based diagnostic model.

Methods: In this prospective case-control study, 116 allo-HSCT recipients (61 with oGVHD and 55 without) and 47 healthy controls were enrolled. A sandwich antibody array was used to screen differentially expressed proteins in a pilot cohort (n = 4 per group), followed by pathway enrichment analysis. Ocular surface parameters and serum levels of NLRP3, TLR4, CCL2, IL-18, IL-6, and TNF-α were measured. Linear correlation, logistic regression, receiver operating characteristic (ROC) analyses, and internal bootstrap validation were performed to evaluate diagnostic performance. A cytokine-based risk score model was established.

Results: Thirty-four upregulated proteins were enriched in immune and inflammatory pathways. Patients with oGVHD exhibited severe dry eye features and significantly higher serum levels of NLRP3, TLR4, CCL2, IL-18, and IL-6 (all p < 0.001), which inversely correlated with ocular surface parameters. A logistic model combining these five cytokines achieved excellent diagnostic accuracy (AUC = 0.960). Internal 10-fold cross-validation with 1,000 bootstrap iterations yielded a consistent mean AUC of 0.953, confirming model robustness. A simplified risk score stratified patients into low-, intermediate-, and high-risk categories with strong discriminatory power (p < 0.001).

Conclusion: A serum panel of NLRP3, TLR4, CCL2, IL-18, and IL-6 demonstrates high diagnostic accuracy and stability for oGVHD. As the diagnostic cutoffs were derived from the same dataset, potential overfitting cannot be excluded, and independent validation in larger multicenter cohorts is warranted.

Background: Glioblastoma (GBM) is the most aggressive primary tumor of the adult central nervous system, not only characterized by rapid proliferation and diffuse brain infiltration but also by a pronounced pro-inflammatory microenvironment that fuels tumor progression and therapeutic resistance. Current standard-of-care, surgical resection followed by radiotherapy and chemotherapy, offers limited survival benefit, partly due to inflammation-driven invasion and immune evasion. The Hippo signaling pathway, a critical regulator of cell proliferation, apoptosis, and tissue homeostasis, has recently been implicated in inflammatory signaling, making it an attractive therapeutic target.

Purpose: In this study, we investigated the anti-inflammatory and anti-invasive properties of 1,3,6-tri-O-galloyl-α-D-glucose (αTGG), the α-anomer of βTGG from Terminalia chebula, in comparison with pharmacological Hippo pathway inhibitors IAG933, VT107, and GNE7883.

Results: To mimic the inflammatory milieu associated with GBM, U87 cells were treated with Concanavalin A (ConA), which induced phosphorylation of ERK and IκB, key mediators of MAPK and NF-κB inflammatory pathways. Both αTGG and Hippo pathway inhibitors effectively suppressed these phosphorylation events, with VT107 showing the strongest effect. ConA exposure downregulated Hippo pathway downstream effectors (AXL, CTGF, CYR61) in a TEAD-dependent manner, highlighting the interplay between Hippo signaling and inflammatory transcriptional control. Importantly, αTGG and VT107 also significantly attenuated ConA-induced activation of proMMP-2 to MMP-2 and reduced the expression of multiple pro-inflammatory mediators, including COX2, CCL22, CCR2, CCR4, CXCL10, CXCL12, CXCR1, FASLG, IFNG, IL13, and IL17A.

Conclusion: These findings underscore the dual anti-inflammatory and anti-invasive actions of αTGG, positioning it as a promising candidate for targeting inflammation-driven GBM progression through modulation of Hippo pathway activity.

Background: Spinal cord injury (SCI) triggers a intense inflammatory response that hinders the success of cell transplantation therapies. Immortalised Schwann cells (iSCs) offer a renewable cell source, but their response to inflammation is poorly understood. Wnt3a regulates neural stem cells, but its role in modulating inflammatory responses in iSCs remains unclear.

Methods: Rat Schwann cells (SCs) were immortalised using SV40Tag. An inflammatory model was established by treating iSCs with LPS, in the presence or absence of Wnt3a protein. The inflammatory response, apoptosis, proliferation, and migration were assessed using quantitative PCR (qPCR), Western blotting, immunofluorescence, CCK-8 assay, TUNEL staining, flow cytometry, and scratch wound healing assay. An acute spinal cord injury model in rats was utilised for in vivo validation.

Results: This study shows that immortalized Schwann cells share some genotypic similarity with primary Schwann cells, but have a much faster proliferation rate than Schwann cells, which can be better used for neurological disease-related research. In addition, in the LPS-induced inflammatory environment, Wnt3a was able to inhibit the expression of IL-1β in immortalized Schwann cells, and enhance the expression of TGF-β by activating NF-κB. More importantly, Wnt3a inhibited the level of apoptosis in the inflammatory environment and promoted the proliferation and migration ability of cells, which also enhanced the function of immortalized Schwann cells.

Conclusion: Wnt3a modulates the inflammatory response in iSCs, primarily through NF-κB-mediated upregulation of TGF-β, and promotes iSC survival and function. The combination of iSCs and Wnt3a presents a promising strategy for improving cell transplantation therapy for SCI.

Purpose: Rheumatoid arthritis (RA) affects millions of people worldwide and causes chronic joint pain with incompletely understood pathogenesis and challenging management. Myosin light chain 1 (MYL1) a muscle regulatory protein, has an unknown role in RA pathogenesis.

Methods: We analyzed transcriptomic data from RA patients and healthy controls in the Gene Expression Omnibus (GEO). Using least absolute shrinkage and selection operator (LASSO) regression and random forest, we identified differentially expressed genes (DEGs). Diagnostic performance was assessed using receiver operating characteristic (ROC) curves and area under the curve (AUC). To explore potential mechanisms, we conducted functional enrichment and immune-infiltration analyses. We further validated MYL1 expression in a rat RA model using qRT-PCR and Western blotting.

Results: We found MYL1 significantly downregulated in RA with high diagnostic value (AUC > 0.8). Enrichment analyses revealed its involvement in muscle structure development, immune regulation, and calcium signaling pathways. CIBERSORT analysis indicated associations with immune cell infiltration, particularly regulatory T cells, activated natural killer (NK) cells, and M1 macrophages. The rat model confirmed reduced MYL1 expression at both mRNA (p < 0.001) and protein (p = 0.009) levels, consistent with human data.

Conclusion: MYL1 is consistently downregulated in RA and may serve as a potential diagnostic biomarker. The results indicate that MYL1 may be involved in the pathological process of RA through calcium signaling, muscle function, and immune cell regulation. However, further clinical and mechanistic studies are warranted.

Background: In the wake of COVID-19, a resurgence of Mycoplasma pneumoniae pneumonia (MPP) has emerged globally since mid-2023. However, the clinical manifestations and immune responses following infection vary across different age groups of pediatric patients (infants, preschoolers and school-aged children), increasing the complexity of diagnosis and treatment.

Methods: This study retrospectively analyzed serum cytokine levels in 40 healthy children and 87 MPP patients, with additional cytokine profiling of bronchoalveolar lavage fluid (BALF) in severe cases, combining KEGG pathway analysis to investigate age-related immune patterns. SARS-CoV-2 antibody levels were further detected in these MPP patients, followed by Spearman correlation analysis to assess their correlation with cytokines in MPP children.

Results: Age-specific cytokine patterns emerged in MPP children. In 0-2 years, cytokines enriched in IL-17, TLR, and TNF pathways were upregulated in MPP groups compared to controls, while in 6-12 years, cytokines enriched in TLR, RLR, and JAK-STAT pathways were downregulated in MPP groups. Serum patterns in 3-5 years resembled those in 0-2 years, but BALF aligned with 6-12 years. SARS-CoV-2 IgG positively correlated with TWEAK, IL-22, IL-16, IL-12p40, CCL7, and CD152 in 0-2 years (P < 0.05), but negatively with CCL13 in 6-12 years (P < 0.01).

Conclusion: Overall, the immune pattern in children with MPP is age-specific and severity-dependent. Higher levels of SARS-CoV-2 IgG are associated with a more robust and mature anti-infective immune response in younger MPP patients, while in older children, besides providing immune memory against pathogens, SARS-CoV-2 IgG also appears to plant a landmine of immune exhaustion.

Purpose: To develop and externally validate an interpretable machine learning model for preoperative prediction of Gangrenous cholecystitis (GC) using multicenter clinical data.

Patients and methods: This retrospective multicenter study included 744 patients with cholecystitis who underwent cholecystectomy at one institution, split into training (n=521) and testing (n=223) cohorts, and a temporal external validation cohort of 300 patients from a second center. Twenty preoperative variables were screened by LASSO regression and Boruta algorithm; predictors selected by both were used to construct six machine learning models. Model performance was assessed via AUC, calibration, and decision curve analysis. SHAP analysis provided model interpretability.

Results: The Random Forest (RF) model demonstrated superior predictive performance, achieving an AUC of 0.893 in the training set, 0.875 in the testing set, and 0.818 in external validation. Calibration and decision curve analyses indicated excellent agreement and clinical benefit. SHAP analysis identified gallbladder wall thickening, C-reactive protein, pericholecystic fluid, white blood cell count, and impacted stone as the most influential predictors, ensuring transparency of model decisions.

Conclusion: In our multicenter cohorts, this interpretable machine learning model showed good discrimination for preoperative risk stratification of gangrenous cholecystitis and acceptable generalizability between centers. By integrating clinical, laboratory, and imaging features and providing explainability, the approach may assist perioperative decision-making when used alongside clinical judgment. Prospective, multicenter evaluations and clinical impact studies are warranted before routine clinical adoption.

Background: Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease. This study aimed to identify novel biomarkers for SSc through an integrated analysis of plasma proteome-wide Mendelian randomization (MR) and transcriptome, as well as to explore the potential mechanisms.

Methods: The data used were obtained from public databases. Initially, key plasma proteins causally associated with SSc were identified through a two-sample MR analysis. Subsequently, based on the key diseases related to both key plasma proteins (genes) and key drugs targeting these proteins (genes), phenotype scanning was conducted to predict potential adverse side effects of key plasma proteins (genes). Single-cell RNA sequencing (scRNA-seq) analysis was performed to identify key cell types in GSE138669 dataset. Differentially expressed genes (DEGs) within key cell types in SSc were intersected with genes encoding key plasma proteins to obtain candidate biomarkers, whose functions were subsequently explored. By analyzing candidate biomarker expression in GSE138669 and GSE181549 datasets, the biomarkers were identified. Further exploration included regulatory network, cellular heterogeneity, and cell trajectory analyses.

Results: Initially, 106 plasma proteins (corresponding to 104 genes) were identified. It was revealed that targeting 12 key plasma proteins (like CD40LG) for treating SSc might lead to side effects related to specific key diseases (like mesothelioma). After recognizing epithelial cells and fibroblasts as key cell types, 8 candidate biomarkers associated with pathways like "proteasome" were identified. Notably, CCL19 and LOXL2 were identified as biomarkers, which exhibited elevated expression in SSc. Regulatory elements such as FOXL1 and hsa-miR-5001-5p were predicted to target biomarkers. Remarkably, differentiation stages of key cell type with heterogeneity and the biomarker expression patterns across these stages might be associated with SSc progression.

Conclusion: CCL19 and LOXL2 were identified as novel biomarkers for SSc, providing insights into the exploration of the disease's pathogenesis and the development of new therapeutic targets.

Background: Perianal Abscess is an inflammatory disease caused by infection in the perianal area, characterized by inflammatory cell infiltration and imbalance of intestinal flora. The herbal medicine anti-inflammatory combination (KYHJ) has therapeutic effects in acute and chronic soft tissue infections, but the specific therapeutic mechanism in perianal inflammatory diseases is unclear. There is a literature evidence showing the role of OSM gene in inflammatory conditions, however this was not previously studied in perianal abscess.

Methods: A perianal inflammation model was constructed in SD rats using 75% glacial acetic acid and treated with different doses of KYHJ; genome-wide changes were detected by RNA sequencing. H&E staining observed pathological states, TUNEL kit detected apoptosis, WB measured apoptotic protein levels, ELISA detected inflammatory factors in serum, and 16S rRNA sequencing analyzed intestinal flora abundance. In vitro, an anal epithelial cell inflammation model induced by LPS was treated with 10% KYHJ-containing serum; EDU assay, flow cytometry, WB, and ELISA were used to detect cell proliferation, apoptosis, related protein levels, and inflammatory factor secretion. Oncostatin M gene was knocked down in rats and overexpressed in epithelial cells for mechanism exploration.

Results: Results showed that KYHJ ameliorated perianal tissue inflammatory infection, inhibited apoptosis, and restored intestinal flora abundance. Initial transcriptome analysis, RT-qPCR and WB performed in this study have additionally supported the role of OSM gene. RNA sequencing linked the tested anti-inflammatory effects of KYHJ to reduced Oncostatin M (OSM) gene expression. RNA transcriptome sequencing showed high Oncostatin M expression in inflamed rats and low expression in the KYHJ group; in vivo knockdown improved perianal inflammation and increased flora abundance. In vitro, KYHJ - containing serum inhibited LPS - induced apoptosis, promoted proliferation, and reduced inflammatory factor secretion, which were reversed by Oncostatin M overexpression.

Conclusion: KYHJ ameliorates perianal inflammatory diseases by targeting Oncostatin M, restoring intestinal flora imbalance, promoting cell proliferation, and inhibiting apoptosis.

Purpose: Dupilumab is known to cause transient, asymptomatic eosinophilia, but in rare cases it can present as eosinophilic pneumonia accompanied by cough. This study reports a distinct manifestation of dupilumab-related eosinophilia presenting as a severe dry cough despite the absence of radiological or clinical evidence of eosinophilic pneumonia.

Patients and methods: A retrospective analysis of clinical data from patients with severe eosinophilic asthma (SEA) treated with dupilumab at the Guangzhou Institute of Respiratory Disease between August 2020 and February 2025 was conducted. Data on clinical manifestations, objective indicators and subjective questionnaires were collected at four time-points: before dupilumab initiation, preceding dupilumab-related cough, during the cough episode, and after cough resolution.

Results: Five patients treated with dupilumab (three males and two females with a mean age of 65.6 ± 9.2 years) developed a severe dry cough and marked eosinophilia (1,130-4,050 cells/μL) without radiologic or clinical evidence of eosinophilic pneumonia. The cough began after one to eleven dupilumab courses. Despite the increase in eosinophils, all patients achieved their personal best FEV1 versus baseline. The symptoms resolved with a short course of systemic corticosteroids (in four patients) or antitussive therapy alone (in one patient).

Conclusion: Dupilumab-related eosinophilia can manifest as a severe, steroid-responsive coughing despite the absence of parenchymal eosinophilic disease.

Biologic therapies such as infliximab and adalimumab have transformed the management of inflammatory bowel disease. However, many patients experience primary or secondary loss of response, often due to the development of anti-drug antibodies. The cause of anti-drug antibody formation is thought to be influenced by genetic variations, with human leukocyte antigen alleles-particularly HLA-DQA1*05-emerging as consistent risk factors for immunogenicity, but other candidate variants may also be of importance. To explore the role of genetic predictors in anti-drug antibody development, we systematically reviewed the literature. A search of Medline, Embase, and the Cochrane Library identified 1944 records, of which 27 studies met inclusion criteria. Across these studies, HLA-DQA1*05 carriage was repeatedly associated with higher antibody formation, lower drug levels, treatment failure, and secondary loss of response. Other HLA alleles and FCGR3A variants were also linked to increased risk, while some haplotypes appeared protective. Findings varied depending on the drug, genetic background, and patient population. The role of concomitant immunomodulator therapy was inconsistent, though some genotypes appeared to benefit. Overall, HLA-DQA1*05 and FCGR3A variants are the most reliable predictors of immunogenicity, particularly in infliximab-treated patients. Future work should prioritize large, multi-ethnic prospective studies with standardized antibody measurements and integrated pharmacogenomic approaches to establish clinical utility.