Tumor Necrosis Factor Ligand Superfamily Research Articles

Sex-biased proteomic regulation in obesity

Abstract Background Obesity is a major risk factor for heart failure with preserved ejection fraction, particularly in women. Obesity-associated inflammation is thought to contribute to this relationship. However, the role of biological sex in the regulation of circulating inflammatory proteins in obesity is not well understood. Purpose We aimed to explore sex differences in the plasma inflammatory protein profile in obese subjects. Methods Clinical data and samples were collected from 450 women and men with a body mass index (BMI) >27 kg/m² without known cardiovascular disease participating in the FAT associated CardiOvasculaR dysfunction study. Obesity was defined as BMI≥30 kg/m². Olink’s Target 96 inflammation panel, which profiles 92 proteins using proximity extension assay technology, was analysed in biobank samples. A comprehensive correlation analysis was performed to describe relationships between protein biomarkers and clinical variables. Gene enrichment analysis was performed to shed light on biological pathways associated with differentially expressed proteins (DEPs). To determine the functional significance of the DEPs, we used the repositories Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Pearson correlation coefficients were calculated to assess linear associations between the DEPs and relevant clinical variables. Results Women and men did not differ by age (49±9 vs 48±9 years), BMI (32.3±4.6 vs 31.6±3.7 kg/m²) or in prevalences of diabetes (both 11%) or obesity (65% vs 62%) (all p>0.05). However, hypertension was more common in men than women (74% vs 52%, p<0.001). In men (n=188), obesity was associated with downregulation of monocyte chemotactic protein 3, tumor necrosis factor (ligand) superfamily member 12, interleukin 10 and protein S100-A12 and with upregulation of neurotrophin-3 (all p<0.05), thereby suggesting a mechanism for the observed impaired inflammatory response and insulin resistance. In women (n=262), obesity was associated with the downregulation of interleukin 7, interleukin 12 subunit beta, interleukin 6, and C-X-C motif chemokine 11, suggesting a state of persistent low-grade inflammation. In addition, the upregulated sulfotransferase 1A1 and SIR2-like protein 2 proteins indicate a physiologic adaptation to oxidative stress and the metabolic excess endemic to obesity. Conclusion We found that the abundance of several circulating inflammatory proteins was altered in presence of obesity, and that the plasma proteomic profile differed by sex. Interestingly, there was no overlap in the DEPs between women and men in the presence of obesity. These findings support the hypothesis that the pathophysiological mechanisms driving obesity-associated inflammation and immune dysregulation differ by sex. In turn, this may aid in the pursuit of discovering sex-specific biomarkers to identify obese individuals at particular risk of heart failure.

Bidirectional two-sample Mendelian randomization analysis unveils causal association between inflammatory cytokines and the risk of diabetic nephropathy

ObjectivePrevious observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis.MethodSummary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings.ResultAmong individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability.ConclusionThe MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

Systemic Immune Factors and Risk of Allergic Contact Dermatitis: A Bidirectional Mendelian Randomization Study.

Skin inflammation and immune regulation have been suggested to be associated with allergic contact dermatitis (ACD) progression, but whether the system's immune regulation is a cause or a potential mechanism is still unknown. This study aims to assess the upstream and downstream of systemic immune factors on ACD within a bidirectional Mendelian-randomization design. A bidirectional two-sample MR analysis was employed to implement the results from genome-wide association studies for 52 system immune factors and ACD. Genetic associations with systemic immune factors and ACD were obtained from the IEU Open GWAS project database. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis, MR-Egger, weighted median, MR-pleiotropy residual sum, and outlier (MR-PRESSO) was also used as the sensitivity analyses. Only Tumor necrosis factor ligand superfamily member 11 (TNFS11) from among 52 systemic immune factors was associated with a protective effect of ACD. However, ACD was associated with a decrease in Interleukin-9 (IL9) and an increase in C-X-C motif chemokine 1 (GROα), Tumor necrosis factor ligand superfamily member 10 (TRAIL), C4, and complement factor B of the assessed systemic immune factors. This study identified TNFS11 as the upstream regulator and IL9, GROα, TRAIL, C4, and complement factor B as the downstream regulator of ACD, providing opportunities for new therapeutic exploitation of ACD. Nonetheless, these associations of systemic immune factors need to be verified in vivo.

Association of asthma with the risk of cardiovascular disease: A Mendelian randomization study

BackgroundAssociation of asthma with the risk of cardiovascular disease has not been fully elucidated. So, this study tried to explore the genetic effect of asthma on five cardiovascular diseases and 90 peripheral cardiovascular proteins to answer the above topic. MethodsInstrumental variables predicting asthma was extracted from its genome-wide association study data. Two-sample and multivariate MR approaches were used to assess the genetic association of exposure factor (i.e., asthma) with outcome factors (i.e., hypertension, atrial fibrillation, angina pectoris, myocardial infarction, heart failure, and 90 peripheral cardiovascular proteins). ResultsFirst, asthma nominally increased the risk of hypertension and atrial fibrillation (OR = 1.009, 95%CI = 1.003–1.016, P = 0.004; OR = 1.074, 95%CI = 1.024–1.127, P = 0.003). Second, of the 90 cardiovascular proteins, asthma was associated with the increased levels of tumor necrosis factor ligand superfamily member 14 and CC motif chemokine 4 (β = 0.145, 95%CI = 0.077–0.212, P = 2.936e-05; β = 0.128, 95%CI = 0.063–0.193, P = 1.036e-04). Third, CC motif chemokine 4 increased the risk of hypertension (P = 0.043); and after adjusting for this protein, asthma still increased the risk of hypertension, but the strength of its P-value changed from 0.004 to 0.011. ConclusionAsthma was a risk factor for hypertension and atrial fibrillation at the genetic level, and CC motif chemokine 4 might play a mediating role in the mechanism by which asthma promoted hypertension. Thus, effective control of asthma may help reduce the risk of some cardiovascular diseases in older adults.

Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming

Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1β, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.

The PerioGene North Study Uncovers Serum Proteins Related to Periodontitis

The sequalae of periodontitis include irreversible degradation of tooth-supporting structures and circulatory spread of inflammatory mediators. However, the serum protein profile in periodontitis is not well described, which is partly attributable to the limited number of studies based on large and well-characterized periodontitis cohorts. This study aims to identify novel, circulating inflammation-related proteins associated with periodontitis within the PerioGene North case-control study, which includes 478 cases with severe periodontitis and 509 periodontally healthy controls. The serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and a panel of 45 inflammation-related proteins were analyzed using targeted proteomics. A distinguishable serum protein profile was evident in periodontitis cases. The protein pattern could separate cases from controls with a sensitivity of 0.81 and specificity of 0.81 (area under the curve = 0.87). Adjusted levels for hs-CRP and 24 of the 45 proteins were different between cases and controls. High levels of hs-CRP and matrix metalloproteinase–12, and low levels of epidermal growth factor (EGF) and oxidized low-density lipoprotein receptor 1 (OLR-1) were detected among the cases. Furthermore, the levels of C-C motif chemokine–19, granulocyte colony-stimulating factor–3 (CSF-3), interleukin-7 (IL-7), and hs-CRP were significantly higher in cases with a high degree of gingival inflammation. The levels of CSF-3 and tumor necrosis factor ligand superfamily member–10 TNFSF-10 were higher in cases with many deep periodontal pockets. The PerioGene North study includes detailed clinical periodontal data and uncovers a distinct serum protein profile in periodontitis. The findings of lower EGF and OLR-1 among the cases are highlighted, as this has not been presented before. The role of EGF and OLR-1 in periodontitis pathogenesis and as possible future biomarkers should be further explored.

Clinical Significance of TNFSF14/LIGHT and CD160 in Gastric Cancer and Peptic Ulcer Dyspepsia.

Previous studies have reported the role of the Herpes Virus Entry Mediator (HVEM) in various cancer including gastric cancer. However, the expression level and clinical significance of CD160 and Tumor Necrosis Factor Ligand Superfamily Member 14 (TNFSF14) pathways in gastric cancer and gastric dyspepsia patients have remained unexplored. The study involved the collection of gastric tissue biopsies from 42 patients with non-ulcerative dyspepsia (NUD) as the control group, 43 gastric cancer (GC) patients, and 48 patients with peptic-ulcerative dyspepsia (PUD). All the patients were endoscopically examined at Imam Khomeini Hospital in Sari, Mazandaran, Iran. The expression levels of TNFSF14 and CD160 mRNA were assessed using quantitative real-time PCR (qPCR) with the SYBR Green method. Statistical analysis was performed to investigate the potential association between the clinical and experimental data. Among the 133 gastric endoscopic biopsies examined, LIGHT exhibited a significant overexpression in GC patients (p-value < 0.01). Moreover, the expression of TNFSF14 was higher in GC patients with stages I and II (p-value<0.05). Furthermore, GC patients with TNM stages III+IV were accompanied by high expression levels of LIGHT (p-value < 0.01) as well as CD160 (p-value<0.05). The expression of CD160 was also higher in younger adults with PUD (p-value<0.05). Whereas TNFSF14 exhibited higher expression in older adults with GC (p-value<0.05). Furthermore, this research provided insights into the potential biological pathways and significant gene enrichment of TNFSF14 and CD160, suggesting the potential role of CD160 and TNFSF14 in the regulation of immune system in GC and PUD. These findings suggest the possible role of LIGHT and CD160 expression in gastric cancer patients in immune dysregulation toward gastric cancer. Targeted immunotherapy that harnessing co-stimulatory molecules like LIGHT and CD160 could be a promising approach in the treatment of GC as well as potential GC tumor markers.

Genetic support for the causal association between 91 circulating inflammatory proteins and atopic dermatitis: A two-sample Mendelian randomization trial.

Atopic dermatitis (AD) is a refractory disease that occurs in clinical practice. One of the most common inflammatory skin diseases, its occurrence and development are related to inflammation. Nevertheless, the precise nature of the relationship between circulating inflammatory proteins and AD remains uncertain. A two-sample MR analysis was performed to determine the causal relationship between the expression of 91 circulating inflammatory proteins and AD by using genome-wide association study (GWAS) summary statistics data from the FinnGen consortia. The robustness of the MR results was assessed by means of sensitivity analysis. The causal relationship between the expression of nine specific circulating inflammatory proteins and AD was corroborated by the inverse variance weighted (IVW) method. The findings indicated that three circulating inflammatory proteins, namely, interleukin-18 receptor 1 [OR (CI)=1.08 (1.05-1.11); p=0.000001)], interleukin-8 [OR (CI)=1.07 (1.00-1.14); p=0.036244)], and tumor necrosis factor ligand superfamily member 14 [OR (CI)=1.05 (1.00-1.10); p=0.036842)], were positively correlated with AD. Additionally, six circulating inflammatory proteins were negatively correlated with AD: the T-cell surface glycoprotein CD5 [OR (CI)=0.89 (0.84-0.95); p=0.000191)], macrophage colony-stimulating factor 1 [OR (CI)=0.93 (0.88-0.99); p=0.031422)], fractalkine [OR (CI)=0.91 (0.85-0.97); p=0.003067)], interleukin-24 [OR (CI)=0.91 (0.83-0.99); p=0.031673)], signaling lymphocytic activation molecule [OR(CI)=0.94 (0.89-1.00); p=0.039818)], and urokinase-type plasminogen activator [OR(CI)=0.95 (0.90-1.00); p=0.037037)]. This study confirms the potential causal relationship between circulating inflammatory proteins and AD and provides guidance for the clinical diagnosis and treatment of AD.

Circulating inflammatory factors and risk causality associated with type 2 diabetic nephropathy: A Mendelian randomization and bioinformatics study.

The main causative factors of diabetic nephropathy (DN), a common complication of diabetes mellitus, are metabolic abnormalities and hemodynamic changes. However, studies have shown that the immune-inflammatory response also plays an important role in DN pathogenesis. Therefore, in this study, we analyzed the causal relationship and immune infiltration between inflammatory factors and DN using Mendelian randomization (MR) and bioinformatics techniques. We analyzed the causal relationship between 91 inflammatory factors and DN using two-sample MR dominated by the results of inverse variance-weighted analysis. Based on the MR analysis, the immune mechanism of inflammatory factors in DN was further explored using immune cell infiltration analysis. MR analysis indicated a positive causal relationship between DN and IL1A, caspase 8 (CASP8), macrophage colony-stimulating factor 1, IL10, STAM-binding protein, and tumor necrosis factor ligand superfamily member 12 (TNFSF12) and a negative causal relationship between DN and cystatin D, fibroblast growth factor 19, neurturin, and TNFSF14. The pathogenic mechanism of CASP8 may involve the recruitment of CD4+ T cells and macrophages for DN infiltration. In this study, we found a causal relationship between DN and IL1A, CASP8, macrophage colony-stimulating factor 1, IL10, STAM-binding protein, TNFSF12, cystatin D, fibroblast growth factor 19, neurturin, and TNFSF14. Bioinformatic immune infiltration analysis further revealed that CASP8 regulates DN by influencing the infiltration of immune cells, such as T cells and macrophages.

Exploring the bidirectional causal associations between pain and circulating inflammatory proteins: A Mendelian randomization study.

Multisite chronic pain (MCP) and site-specific chronic pain (SSCP) may be influenced by circulating inflammatory proteins, but the causal relationship remains unknown. To overcome this limitation, two-sample bidirectional Mendelian randomization (MR) analysis was used to analyse data for 91 circulating inflammatory proteins, MCP and SSCP encompassing headache, back pain, shoulder pain, hip pain, knee pain, stomach abdominal pain and facial pain. The primary MR method used was inverse variance weighting, sensitivity analyses included weighted median, MR pleiotropy residual sum and outlier and the Egger intercept method. Heterogeneity was also detected using Cochrane's Q test and leave-one-out analyses. Finally, a causal relationship between 29 circulating inflammatory proteins and chronic pain was identified. Among these proteins, 14 exhibited a protective effect, including MCP (T-cell surface glycoprotein cluster of differentiation 5), headache (4E-binding protein 1 [4EBP1], cluster of differentiation 40, cluster of differentiation 6 and C-X-C motif chemokine [CXCL] 11), back pain (leukaemia inhibitory factor), shoulder pain (fibroblast growth factor [FGF]-5 and interleukin [IL]-18R1), stomach abdominal pain (tumour necrosis factor [TNF]-α), hip pain (CXCL1, IL-20 and signalling lymphocytic activation molecule 1) and knee pain (IL-7 and TNF-β). Additionally, 15 proteins were identified as risk factors for MCP and SSCP: MCP (colony-stimulating factor 1, human glial cell line-derived neurotrophic factor and IL-17C), headache (fms-related tyrosine kinase 3 ligand, IL-20 receptor subunit α [IL-20RA], neurotrophin-3 and tumour necrosis factor receptor superfamily member 9), facial pain (CXCL1), back pain (TNF), shoulder pain (IL-17C and matrix metalloproteinase-10), stomach abdominal pain (IL-20RA), hip pain (C-C motif chemokine 11/eotaxin-1 and tumour necrosis factor ligand superfamily member 12) and knee pain (4EBP1). Importantly, in the opposite direction, MCP and SSCP did not exhibit a significant causal impact on circulating inflammatory proteins. Our study identified potential causal influences of various circulating inflammatory proteins on MCP and SSCP and provided promising treatments for the clinical management of MCP and SSCP.

Morphologic, cytometric, quantitative transcriptomic and functional characterisation provide insights into the haemocyte immune responses of Pacific abalone (Haliotis discus hannai).

In recent years, the abalone aquaculture industry has been threatened by the bacterial pathogens. The immune responses mechanisms underlying the phagocytosis of haemocytes remain unclear in Haliotis discus hannai. It is necessary to investigate the immune mechanism in response to these bacterial pathogens challenges. In this study, the phagocytic activities of haemocytes in H. discus hannai were examined by flow cytometry combined with electron microscopy and transcriptomic analyses. The results of Vibrio parahaemolyticus, Vibrio alginolyticus and Staphylococcus aureu challenge using electron microscopy showed a process during phagosome formation in haemocytes. The phagocytic rate (PP) of S. aureus was higher than the other five foreign particles, which was about 63%. The PP of Vibrio harveyi was about 43%, the PP peak of V. alginolyticus in haemocyte was 63.7% at 1.5h. After V. parahaemolyticus and V. alginolyticus challenge, acid phosphatase, alkaline phosphatase, total superoxide dismutase, lysozyme, total antioxidant capacity, catalase, nitric oxide synthase and glutathione peroxidase activities in haemocytes were measured at different times, differentially expressed genes (DEGs) were identified by quantitative transcriptomic analysis. The identified DEGs after V. parahaemolyticus challenge included haemagglutinin/amebocyte aggregation factor-like, supervillin-like isoform X4, calmodulin-like and kyphoscoliosis peptidase-like; the identified DEGs after V. alginolyticus challenge included interleukin-6 receptor subunit beta-like, protein turtle homolog B-like, rho GTPase-activating protein 6-like isoform X2, leukocyte surface antigen CD53-like, calponin-1-like, calmodulin-like, troponin C, troponin I-like isoform X4, troponin T-like isoform X18, tumor necrosis factor ligand superfamily member 10-like, rho-related protein racA-like and haemagglutinin/amebocyte aggregation factor-like. Some immune-related KEGG pathways were significantly up-regulated or down-regulated after challenge, including thyroid hormone synthesis, Th17 cell differentiation signalling pathway, focal adhesion, melanogenesis, leukocyte transendothelial migration, inflammatory mediator regulation of TRP channels, ras signalling pathway, rap1 signalling pathway. This study is the first step towards understanding the H. discus hannai immune system by adapting several tools to gastropods and providing a first detailed morpho-functional study of their haemocytes.

Genetically predicted 91 circulating inflammatory proteins in relation to risk of urological malignancies: a Mendelian randomization study.

Urological malignancies, including kidney, bladder, and prostate cancer, are major health concerns worldwide. Inflammation has been implicated in the pathogenesis of these cancers, and circulating inflammatory proteins may play a role in their development. However, the causal relationship between specific plasma proteins and urological malignancies remains unclear. We performed a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS). Instrumental variables representing genetic variants associated with circulating inflammatory proteins were used to infer causality on the risk of kidney, bladder, and prostate cancer. Four MR methods were utilized to provide robust effect estimates. Our analysis identified several plasma proteins associated with a lower risk of kidney and bladder cancer, including Eukaryotic translation initiation factor 4E-binding protein 1, Caspase 8, Natural killer cell receptor 2B4, and Tumor necrosis factor ligand superfamily member 12. However, after adjusting for multiple testing, these associations did not remain statistically significant. For prostate cancer, CUB domain-containing protein 1 and Interleukin-10 receptor subunit beta were found to be protective, while Glial cell line-derived neurotrophic factor and SIR2-like protein 2 were identified as risk factors. After FDR adjustment, none of the inflammatory proteins were found to be significantly associated with a lower risk of prostate cancer. Our findings suggest that certain plasma proteins may be involved in the development of urological malignancies. Mendelian randomization provides a useful framework for investigating causal relationships between inflammatory proteins and urological cancers, offering potential insights into their underlying biology and therapeutic targets.

Association of overexpression of TNF receptor superfamily members (CD40, BAFFR, LTβR and RANK) with favorable prognosis in patients with colorectal adenocarcinoma.

e15516 Background: Numerous studies by our and other groups have highlighted the implication of NF-κB in colorectal cancer (CRC) through the deterioration of classical and alternative pathway signaling. The alternative pathway of NF-κB can be activated by members of TNF superfamily, such as lymphotoxin β (LTβ), tumor necrosis factor ligand superfamily member 5 (CD40L), B-cell activation factor (BAFF) and receptor activator of NF-κB ligand (RANKL). We have previously shown that alternative pathway of NF-κΒ is deteriorated in CRC. In the present study, we investigated the clinical significance of the aforementioned receptors in patients with CRC as well as their relation with effector transcription factors NF-κB2 and RELB. Methods: Gene expression of CD40, BAFFR, LT β R, RANK, NF- κ B2 and RELB, quantified by using real-time qRT-PCT and specific primers and probes, was assessed in 97 cancerous and 61 paired non-neoplastic tumor-adjacent formalin-fixed paraffin-embedded (FFPE) tissue specimens from CRC patients who were surgically managed in the University Hospital of Patras, Greece. Concurrently, we assessed protein expression of the same molecules by immunohistochemistry in the same cohort of patients. Both, mRNA and protein levels of the receptors were analyzed in association with clinicopathological parameters and clinical outcome of the patients in terms of time to disease progression. Results: Cytoplasmic expression of all molecules was higher in cancer compared to tumor-adjacent epithelial cells ( p= 0.047 for CD40, p= 0.007 for BAFFR, p&lt; 0.001 for LTβR and p= 0.003 for RANK) and in stromal cells ( p&lt; 0.001 for all molecules), while the reverse pattern (lower in neoplastic epithelial cells) was observed for nuclear expression ( p&lt; 0.001 for all molecules). Similarly, mRNA levels of LTβR and RANK were higher in cancer compared to adjacent non-neoplastic tissues ( p= 0.019 and p= 0.037, respectively). Notably, patients with high mRNA levels of all studied receptors had significantly longer time to disease progression ( p= 0.026 for CD40, p= 0.023 for BAFFR, p= 0.027 for LTβR and p= 0.038 for RANK). In addition, mRNA levels of BAFFR, LTβR and RANK levels were higher in ulcerative tumors compared to polypoid tumors ( p= 0.002, p= 0.005 and p= 0.011, respectively). RELB mRNA levels were positively correlated with mRNA levels of CD40, BAFFR and LTβR in cancerous ( p&lt; 0.001 for all molecules) and non-cancerous tissues (p &lt; 0.001 for all molecules). Surprisingly, NF-κB2 mRNA levels were positively correlated with BAFFR and LTβR mRNA levels in malignant tissues, while in non-malignant tissues were positively correlated with all receptors’ mRNA levels ( p&lt; 0.001 for all molecules). Conclusions: This study suggests a prognostic value for CD40, BAFFR, LTβR and RANK expression in patients with CRC and further supports the role of the alternative pathway of NF-κB in CRC.

Evidence supported by Mendelian randomization: impact on inflammatory factors in knee osteoarthritis.

Prior investigations have indicated associations between Knee Osteoarthritis (KOA) and certain inflammatory cytokines, such as the interleukin series and tumor necrosis factor-alpha (TNFα). To further elaborate on these findings, our investigation utilizes Mendelian randomization to explore the causal relationships between KOA and 91 inflammatory cytokines. This two-sample Mendelian randomization utilized genetic variations associated with KOA from a large, publicly accessible Genome-Wide Association Study (GWAS), comprising 2,227 cases and 454,121 controls of European descent. The genetic data for inflammatory cytokines were obtained from a GWAS summary involving 14,824 individuals of European ancestry. Causal relationships between exposures and outcomes were primarily investigated using the inverse variance weighted method. To enhance the robustness of the research results, other methods were combined to assist, such as weighted median, weighted model and so on. Multiple sensitivity analysis, including MR-Egger, MR-PRESSO and leave one out, was also carried out. These different analytical methods are used to enhance the validity and reliability of the final results. The results of Mendelian randomization indicated that Adenosine Deaminase (ADA), Fibroblast Growth Factor 5(FGF5), and Hepatocyte growth factor (HFG) proteins are protective factors for KOA (IVWADA: OR = 0.862, 95% CI: 0.771-0.963, p = 0.008; IVWFGF5: OR = 0.850, 95% CI: 0.764-0.946, p = 0.003; IVWHFG: OR = 0.798, 95% CI: 0.642-0.991, p = 0.042), while Tumor necrosis factor (TNFα), Colony-stimulating factor 1(CSF1), and Tumor necrosis factor ligand superfamily member 12(TWEAK) proteins are risk factors for KOA. (IVWTNFα: OR = 1.319, 95% CI: 1.067-1.631, p = 0.011; IVWCSF1: OR = 1.389, 95% CI: 1.125-1.714, p = 0.002; IVWTWEAK: OR = 1.206, 95% CI: 1.016-1.431, p = 0.032). The six proteins identified in this study demonstrate a close association with the onset of KOA, offering valuable insights for future therapeutic interventions. These findings contribute to the growing understanding of KOA at the microscopic protein level, paving the way for potential targeted therapeutic approaches.

The causal effect of inflammatory proteins and immune cell populations on diabetic nephropathy: evidence from Mendelian randomization.

Diabetic nephropathy (DN) is one of the diabetic microvascular complications with complex pathophysiology, and exploring the landscape of immune dysregulation in DN is valuable for pathogenesis and disease treatment. We crystallized possible inflammatory exposures into 91 circulating inflammatory proteins and 109 blood immune cells; and assessed the causal relationship between inflammation and DN using Mendelian randomization (MR). Based on publicly available genetic data, we explored causal associations between inflammation and DN risk by two-sample MR analysis. Genome-wide association study (GWAS) summary statistics for 91 circulating inflammatory proteins, 109 immune cells absolute counts, and DN were acquired from the GWAS Catalog. Inverse Variance Weighted (IVW) was the main MR method, while MR-Egger and MR-pleiotropy residuals and outliers (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q was used to test for heterogeneity. The leave-one-out method ensured the stability of the MR results. This study revealed that higher levels of TNF-related activation-induced cytokine and tumor necrosis factor ligand superfamily member 14 were possibly associated with the increased risk of DN according to the IVW approach, with estimated odds ratios (OR) of 1.287 (95% confidence interval [CI] 1.051 to 1.577, P = 0.015) and 1.249 (95% CI 1.018 to 1.532, P = 0.033). Five immune cell traits were identified that might be linked to increased DN risk, including the higher absolute counts of HLA DR+ natural killer cell (OR = 1.248, 95% CI 1.055 to 1.476, P = 0.010), IgD+ CD38+ B cell (OR = 1.148, 95% CI 1.033 to 1.276, P = 0.010), CD25++ CD8+ T cell (OR = 1.159, 95% CI 1.032 to 1.302, P = 0.013), CD4- CD8- T cell (OR = 1.226, 95% CI 1.032 to 1.457, P = 0.020), and IgD- CD38- B cell (OR = 1.182, 95% CI 1.009 to 1.386, P = 0.039). In addition, elevated levels of interleukin-1 alpha (OR = 0.712, 95% CI 0.514 to 0.984, P = 0.040) and unswitched memory B cell (OR = 0.797, 95% CI 0.651 to 0.974, P = 0.027) may reduce the risk of developing DN. We identified inflammation-related exposures that may be associated with the risk of DN at the level of genetic prediction, which contributes to a better understanding of the etiologic of DN and facilitates the development of targeted therapies for DN.

Molecular characterization, antibacterial and immunoregulatory activities of liver-expressed antimicrobial peptide 2 in black rockfish, Sebastes schlegelii

LEAP2 (liver expression antimicrobial peptide 2), is an antimicrobial peptide widely found in vertebrates and mainly expressed in liver. LEAP2 plays a vital role in host innate immunity. In teleosts, a number of LEAP2 homologs have been reported, but their in vivo effects on host defense are still limited. In this study, a LEAP2 homolog (SsLEAP2) was identified from black rockfish, Sebastes schlegelii, and its structure, expression as well as biological functions were analyzed. The results showed that the open reading frame of SsLEAP2 is 300 bp, with a 5′- untranslated region (UTR) of 375 bp and a 3’ - UTR of 238 bp. The deduced amino acid sequence of SsLEAP2 shares the highest overall identity (96.97%) with LEAP2 of Sebastes umbrosus. SsLEAP2 possesses conserved LEAP2 features, including a signal peptide sequence, a prodomain and a mature peptide, in which four well-conserved cysteines formed two intrachain disulphide domain. The expression of SsLEAP2 was highest in liver and could be induced by experimental infection with Listonella anguillarum, Edwardsiealla piscicida and Rock bream iridovirus C1 (RBIV-C1). Recombinant SsLEAP2 (rSsLEAP2) purified from Escherichia coli was able to bind with various Gram-positive and Gram-negative bacteria. Further analysis showed that rSsLEAP2 could enhance the respiratory burst activity, and induce the expression of immune genes including interleukin 1-β (IL-1β) and serum amyloid A (SAA) in macrophages; additionally, rSsLEAP2 could also promote the proliferation and chemotactic of peripheral blood lymphocytes (PBLs). In vivo experiments indicated that overexpression of SsLEAP2 could inhibit bacterial infection, and increase the expression level of immune genes including IL-1β, tumor necrosis factor ligand superfamily member 13B (TNF13B) and haptoglobin (HP); conversely, knock down of SsLEAP2 promoted bacterial infection and decreased the expression level of above genes. Taken together, these results suggest that SsLEAP2 is a novel LEAP2 homolog that possesses apparent antibacterial activity and immunoregulatory property, thus plays a critical role in host defense against pathogens invasion.

TNFSF14 mediates the impact of docosahexaenoic acid on atopic dermatitis: a Mendelian randomization study.

While current research suggests potential value for docosahexaenoic acid (DHA) in the prevention and management of atopic dermatitis (AD), the causal relationship between DHA and AD remains unclear, and the underlying mechanisms are not well understood. To investigate the potential causal relationship between DHA and AD, as well as to explore potential mediating mechanisms, we employed the Mendelian randomization (MR) methods. To study these potential relationships, we conducted MR analysis using publicly available Genome-Wide Association Studies (GWAS) data. Effect estimates were computed using the random-effects inverse-variance weighted method. Our study demonstrates a negative correlation between DHA levels and AD risk (OR: 0.915, 95% CI: 0.858-0.975, p=0.007). Furthermore, in MR analysis using tumor necrosis factor ligand superfamily member 14 (TNFSF14) levels as an outcome, DHA levels also show a negative association with TNFSF14 levels (OR: 0.933, 95% CI: 0.879-0.990, p=0.022). Subsequently, we performed further analysis to explore the relationship between TNFSF14 and AD risk, revealing a positive correlation (OR: 1.069, 95% CI: 1.005-1.137, p=0.033). This suggests a potential mediating role of TNFSF14 in the impact of DHA on AD risk. In summary, our study employs MR analysis to offer genetic evidence indicating a potential role of DHA in reducing the risk of AD, as well as opening avenues for further in-depth investigation into potential mechanisms. These findings emphasize the importance of ongoing research in this field.

The genetic relationships between immune cell traits, circulating inflammatory proteins and preeclampsia/eclampsia.

Preeclampsia/eclampsia (PE), a critical complication during pregnancy, has been suggested to correlate with immune cell phenotypes and levels of circulating inflammatory proteins. Our study aimed to employ a two-sample mendelian randomization (MR) analysis to assess the potential causal effects of immune cell phenotypes and circulating inflammatory proteins on the onset of PE. We utilized summary-level data from genome-wide association studies (GWAS). This included statistics for 371 immune cell phenotypes from 3,757 individuals in the Sardinian founder population, and data on 91 circulating inflammatory proteins from 14,824 European ancestry participants. Additionally, genetic associations related to PE were extracted from the FinnGen consortium, involving 1,413 cases and 287,137 controls. We applied inverse variance weighting (IVW) and supplementary methods like MR-Egger, weighted median, and weighted mode to comprehensively assess potential causal links. Our analysis revealed significant causal associations of several immune cells type and inflammatory proteins with PE. Out of the immune cell phenotypes analyzed, six immune phenotypes emerged as significant risk factors (p <0.01), mainly include CD4 on activated and secreting CD4 regulatory T cells, CD28 on CD39+ CD4+ T cells, CD127- CD8+ T cell absolute cell (AC) counts, HLA DR on HLA DR+ CD8+ T cell, CD66b on CD66b++ myeloid cells, and HLA DR on dendritic cells. And ten were identified as protective factors (p <0.01). Such as CD45 on CD33br HLA DR+ CD14-, CD33+ HLA DR+ AC, CD33+ HLA DR+ CD14- AC, CD33+ HLA DR+ CD14dim AC, CD27 on CD24+ CD27+ B cell, CD20- CD38- %B cell, IgD- CD24- %B cell CD80 on plasmacytoid DC, CD25 on CD4+ T cell, and CD25 on activated & secreting CD4 regulatory T cell. Furthermore, among the inflammatory proteins studied, five showed a significant association with PE, with three offering protective effects mainly include that C-X-C motif chemokine 1, tumor necrosis factor ligand superfamily member 14, and C-C motif chemokine 19 and two exacerbating PE risk such as STAM-binding domain and Interleukin-6 (p <0.05). Our study highlights the pivotal roles played by diverse immune cell phenotypes and circulating inflammatory proteins in the pathophysiology of PE. These findings illuminate the underlying genetic mechanisms, emphasizing the criticality of immune regulation during pregnancy. Such insights could pave the way for novel intervention strategies in managing PE, potentially enhancing maternal and neonatal health outcomes.

Role of inflammatory cytokine in mediating the effect of plasma lipidome on epilepsy: a mediation Mendelian randomization study.

Epilepsy is one of the most prevalent serious brain disorders globally, impacting over 70 million individuals. Observational studies have increasingly recognized the impact of plasma lipidome on epilepsy. However, establishing a direct causal link between plasma lipidome and epilepsy remains elusive due to inherent confounders and the complexities of reverse causality. This study aims to investigate the causal relationship between specific plasma lipidome and epilepsy, along with their intermediary mediators. We conducted a two-sample Mendelian randomization (MR) and mediation MR analysis to evaluate the causal effects of 179 plasma lipidomes and epilepsy, with a focus on the inflammatory cytokine as a potential mediator based on the genome-wide association study. The primary methodological approach utilized inverse variance weighting, complemented by a range of other estimators. A set of sensitivity analyses, including Cochran's Q test, I 2 statistics, MR-Egger intercept test, MR-PRESSO global test and leave-one-out sensitivity analyses was performed to assess the robustness, heterogeneity and horizontal pleiotropy of results. Our findings revealed a positive correlation between Phosphatidylcholine (18:1_18:1) levels with epilepsy risk (OR = 1.105, 95% CI: 1.036-1.178, p = 0.002). Notably, our mediation MR results propose Tumor necrosis factor ligand superfamily member 12 levels (TNFSF12) as a mediator of the relationship between Phosphatidylcholine (18,1_18:1) levels and epilepsy risk, explaining a mediation proportion of 4.58% [mediation effect: (b = 0.00455, 95% CI: -0.00120-0.01030), Z = 1.552]. Our research confirms a genetic causal relationship between Phosphatidylcholine (18:1_18:1) levels and epilepsy, emphasizing the potential mediating role of TNFSF12 and provide valuable insights for future clinical investigations into epilepsy.

Associations between TNFSF13B polymorphisms and primary Sjögren's syndrome susceptibility in primary Sjögren's syndrome patients: A meta-analysis.

B-cell activating factor (BAFF) is a key regulator of primary Sjögren's syndrome (pSS), which is characterized by B-lymphocyte hyperactivity. BAFF, also known as tumor necrosis factor ligand superfamily member 13B, is encoded by TNFSF13B. This study aimed to explore the possible relationships between five single-nucleotide polymorphisms (SNPs) of TNFSF13B (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) and pSS susceptibility. We searched the following databases for articles on TNFSF13B polymorphism and pSS published up to January 2023: PubMed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang. The odds ratios (with 95% confidence intervals) of genotypes and SNP alleles of TNFSF13B were investigated in patients with pSS to determine their relationships with pSS. This meta-analysis employing the fixed-effect model comprised three studies of pSS patients and randomly selected healthy controls (HCs), revealing statistically significant relationships between pSS susceptibility and two SNPs: rs1041569 and rs12583006. Because rs1041569 was not in Hardy-Weinberg equilibrium in the HC group, it was eliminated from the analysis. Polymorphisms in the BAFF (TNFSF13B) gene were related to vulnerability to pSS among pSS patients and HCs alike. The SNP rs12583006 was significantly related to pSS susceptibility in pSS patients.