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At least 19 recordsLinked to original sources
PubMed2025

Genetic predisposition to systemic inflammatory proteins is causally associated with inflammatory bowel disease: Insights from multi-omics association study and single-cell RNA-sequencing analysis.

Systemic inflammatory proteins have been reported to be related to inflammatory bowel disease (IBD) in previous observational research. However, their causal links remain obscure. Herein, we performed a Mendelian randomization (MR) analysis to analyze the causality between systemic inflammatory proteins and IBD. Genetic variants related to systemic inflammatory proteins were extracted from a meta-analysis of genome-wide association study (GWAS) data of 8293 European participants. Summary statistics of IBD diverse subtypes were obtained from the international IBD genetic consortium (IIBDGC). We conducted multi-omics method and MR study to detect the causal links through integrating GWAS and protein quantity trait loci (pQTL) data. Inverse variance weighted (IVW) approach was utilized as the dominated analysis method. Moreover, complementary approaches such as MR-Egger intercept test, Cochran Q test and leave-one-out analysis were utilized to validate pleiotropy and heterogeneity. Finally, single-cell RNA-sequencing analysis was performed to detect the expression of significant genes. For IBD, IVW estimates suggested that genetically predicted IL-10 and IL-13 were suggestively associated with an elevated risk of IBD (IL-10: OR: 1.12, 95% CI: 1.00-1.24, P = .04; IL-13: OR: 1.09, 95% CI: 1.01-1.18, P = .023), while CXCL10 was suggestively linked to a lower risk of IBD (CXCL10: OR: 0.90, 95% CI: 0.82-0.99, P = .037). For Crohn disease (CD), the IVW approach provided evidence to sustain that genetically determined IL-13 and CCL3 had a suggestive association with a higher risk of CD (IL-13: OR: 1.13, 95% CI: 1.02-1.26, P = .023; CCL3: OR: 1.22, 95% CI: 1.03-1.45, P = .018). Sensitivity analysis did not explore any heterogeneity and pleiotropy. Our findings supported the causal relationships between 4 specific inflammatory proteins (IL-10, IL-13, CXCL10, and CCL3) and the risk of IBD and CD, thereby providing promising biomarkers of various subtypes stratification and new insights for the prevention and therapeutic target of IBD.

Humans↗
PubMed2024

Identification of interaction partners of outer inflammatory protein A: Computational and experimental insights into how Helicobacter pylori infects host cells.

Outer membrane proteins (OMPs) play a key role in facilitating the survival of Helicobacter pylori within the gastric tissue by mediating adherence. Among these proteins, Outer inflammatory protein A (OipA) is a critical factor in H. pylori colonization of the host gastric epithelial cell surface. While the role of OipA in H. pylori attachment and its association with clinical outcomes have been established, the structural mechanisms underlying OipA's action in adherence to gastric epithelial cells remain limited. Our study employed experimental and computational approaches to investigate the interaction partners of OipA on the gastric epithelial cell surface. Initially, we conducted a proteomic analysis using a pull-down assay with recombinant OipA and gastric epithelial cell membrane proteins to identify the OipA interactome. This analysis revealed 704 unique proteins that interacted with OipA. We subsequently analyzed 16 of these OipA partners using molecular modeling tools. Among these 16 partners, we highlight three human proteins, namely Hepatocyte growth factor (HGF), Mesenchymal epithelial transition factor receptor (Met), and Adhesion G Protein-Coupled Receptor B1 (AGRB1) that could play a role in H. pylori adherence to the gastric epithelial cell surface with OipA. Collectively, these findings reveal novel host interactions mediated by OipA, suggesting their potential as therapeutic targets for combating H. pylori infection.

Helicobacter pylori↗
PubMed2026

Two-sample Mendelian randomization study of gut microbiota and inflammatory proteins: Predictive, preventive, and personalized treatment for migraine.

The human gut microbiota is increasingly recognized as a significant factor in the pathogenesis of migraine, potentially via inflammatory pathways. Identifying specific human gut microbiota components associated with migraines, along with the investigation of particular inflammatory proteins, is essential for advancing primary prediction, targeted prevention, and personalized treatment strategies for migraines. We conducted a two-sample Mendelian randomization study using publicly available summary statistics from genome-wide association studies. Data for 473 human gut microbiota taxa were obtained from the Finnish national health survey conducted by the National Institute for Health and Welfare study (FINRISK, n = 5959 European participants). Genome-wide association study data (https://www.ebi.ac.uk/gwas/) for 91 circulating inflammatory proteins were obtained from 14,824 participants across 11 cohorts using the Olink Target 96 Inflammation panel. Migraine outcome data were obtained from the FinnGen R12 release, with cases defined using ICD-10 code G43. All genome-wide association study analyses were adjusted for sex, age, genotyping batch, and 10 genetic principal components to control population stratification (genomic inflation factors: 1.00–1.05). Inverse variance-weighted Mendelian randomization was the primary analysis method, with Mendelian randomization-Egger, weighted median, and mode-based methods as sensitivity analyses. Two-step Mendelian randomization mediation analysis quantified the proportion of the effects of human gut microbiota on migraine that are mediated through inflammatory proteins. Thirty-seven bacterial genera were found to be associated with migraine using the inverse variance-weighted method. Of these, 18 genera exhibited a negative association, while 19 genera demonstrated a positive association with migraine risk. Additionally, eight inflammatory proteins were found to increase the risk of migraine. Among human gut microbiota, four were observed to reduce inflammatory protein levels, whereas another four were associated with increased inflammatory protein levels. Additionally, five gut microbiota were identified to influence migraine through inflammatory proteins in both Mendelian randomization analyses. Specifically, Actinobacteria, Brachyspiraceae, CAG-269 sp001915995, and Paraglaciecola were found to affect migraine outcomes via inflammatory proteins, with mediation proportions of 12%, 19%, 15.5%, and 6.7%, respectively. Lawsonibacter sp002161175 was identified to influence migraine risk through Oncostatin-M and SLAM, with mediation proportions of 15.6% and 11.3%, respectively. Our study elucidated the role of specific human gut microbiota alterations in the pathogenesis of migraine and highlighted the mediating effects of inflammatory proteins. Targeting these particular human gut microbiota alterations offers a promising strategy for predictive, preventive, and personalized medicine in migraine management, resulting in substantial clinical advancements.

causality↗
PubMed2026

Exploring Causal Links Between 91 Circulating Inflammatory Proteins and Hashimoto's Thyroiditis: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Increasing evidence has linked inflammation to Hashimoto's thyroiditis (HT) etiology. However, the causal role of circulating inflammatory proteins in HT remains uncertain. To investigate this, we conducted a bidirectional Mendelian randomization (MR) study. METHODS: Genetic data for 91 inflammatory proteins and HT were sourced from publicly available GWAS databases. The PhenoScanner database was then searched for pleiotropic SNPs associated with potential confounders. Inverse variance weighted (IVW) analysis was used as the primary analysis, simultaneously supplemented by five sensitivity analyses to strengthen the results. RESULTS: The results revealed that, after false discovery rate (FDR) correction, interleukin (IL)-12p40 was causally associated with increased risk of HT (OR [95% CI] = 1.295 [1.172, 1.431], p = 3.66 × 10-7, PFDR = 3.33×10-5). Conversely, none of the inflammatory proteins was a consequence of HT. CONCLUSION: This study suggests that IL-12p40 is probably one of the factors correlated with HT etiology, contributing to a better understanding of the pathogenesis of HT and underscoring the potential for therapeutic interventions targeting inflammatory proteins.

Humans↗
PubMed2025

Circulating inflammatory proteins as causal drivers and therapeutic targets in asthma: insights from genetic and pathway-based analyses.

OBJECTIVE: To identify circulating inflammatory proteins with potential causal roles in asthma development through integrated genetic and pathway-based analyses, and to evaluate their potential as therapeutic targets. METHODS: We used genetically anchored instrumental variables from 180 protein quantitative trait loci (pQTLs) to assess the causal effects of 91 circulating inflammatory proteins on asthma risk, using large-scale GWAS datasets. Analytical robustness was evaluated through pleiotropy and heterogeneity testing. Functional enrichment and literature-based pathway analyses were performed to support biological plausibility and validate findings. RESULTS: Four proteins showed significant causal effects on asthma: CCL19 and LIFR were protective (OR = 0.89 and 0.91, p&#x2009;&#x2264;&#x2009;6.8E-03), while ARTN and IL6 were associated with increased risk (OR = 1.15 and 1.18, p&#x2009;&#x2264;&#x2009;1.1E-04). We also identified reverse causal effects of asthma on 11 cytokines, including MMP10, TGFB1, IL33, and IL18R1. Most of these proteins were enriched in pathways related to cytokine signaling and immune response (p&#x2009;<&#x2009;0.001). All identified proteins had prior literature support linking them to asthma or airway inflammation. CONCLUSIONS: Our findings highlight a subset of circulating inflammatory proteins that are likely causal in asthma pathogenesis and may serve as promising targets for therapeutic intervention. These results offer novel insights into the immunological mechanisms underlying asthma and support the utility of genetic causal inference in target prioritization.

Asthma↗
PubMed2025

Causal association between 91 circulating inflammatory proteins and primary open-angle glaucoma: a bidirectional Mendelian randomization study.

BACKGROUND: Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach. METHODS: A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders. RESULTS: In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95&#xa0;% CI: 1.04-1.21, P&#xa0;=&#xa0;0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95&#xa0;% CI: 1.06-1.36, P&#xa0;=&#xa0;0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95&#xa0;% CI: 1.02-1.16, P&#xa0;=&#xa0;0.013), and stem cell factor (SCF) (OR: 1.09, 95&#xa0;% CI: 1.03-1.15, P&#xa0;=&#xa0;0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95&#xa0;% CI: 0.82-0.95, P&#xa0;=&#xa0;0.002), interleukin-18 (IL-18) (OR: 0.92, 95&#xa0;% CI: 0.86-0.99, P&#xa0;=&#xa0;0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95&#xa0;% CI: 0.92-1.00, P&#xa0;=&#xa0;0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95&#xa0;% CI: 0.86-0.97, P&#xa0;=&#xa0;0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95&#xa0;% CI: 0.88-1.00, P&#xa0;=&#xa0;0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95&#xa0;% CI: 0.84-0.95, P&#xa0;=&#xa0;4.63&#xa0;&#xd7;&#xa0;10-4), IL-18 (OR: 0.93, 95&#xa0;% CI: 0.89-0.97, P&#xa0;=&#xa0;0.002), IL-18R1 (OR: 0.96, 95&#xa0;% CI: 0.93-0.99, P&#xa0;=&#xa0;0.023), and LIF (OR: 1.18, 95&#xa0;% CI: 1.04-1.34, P&#xa0;=&#xa0;0.013). Sensitivity analyses further supported the robustness of these findings. CONCLUSION: This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the precise biological mechanisms.

Humans↗
PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n&#x2005;=&#x2005;14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-&#x3b2;) were significantly associated with increased OM risk (odds ratio [OR]&#x2005;=&#x2005;1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR]&#x2005;=&#x2005;0.027). Conversely, decreased levels of osteoprotegerin (OR&#x2005;=&#x2005;0.772; 95% CI: 0.671-0.889; FDR&#x2005;=&#x2005;0.015) and adenosine deaminase (OR&#x2005;=&#x2005;0.811; 95% CI: 0.736-0.894; FDR&#x2005;<&#x2005;0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR&#x2005;<&#x2005;0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-&#x3b2; and OM (posterior probability for hypothesis 4&#x2005;=&#x2005;0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-&#x3b2;, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗
PubMed2026

Metabolomic Signatures of Inflammation in Chronic Kidney Disease.

RATIONALE & OBJECTIVE: Inflammation is associated with adverse kidney, cardiovascular, and mortality outcomes. Investigation of the metabolic milieu as it relates to inflammation may provide important insights into these disease processes. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: African American Study of Kidney Disease and Hypertension (AASK), Atherosclerosis Risk in Communities (ARIC) study, and Boston Kidney Biopsy Cohort (BKBC) participants with available metabolomics and inflammatory protein data. PREDICTORS: Baseline blood levels of 718 metabolites. OUTCOMES: Baseline and longitudinal changes in blood levels of tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), tumor necrosis factor-alpha (TNF-&#x3b1;), interferon-gamma (IFN-&#x3b3;), interleukins 6, 8, and 10 (IL-6, IL-8, IL-10), uromodulin (UMOD), and epidermal growth factor (EGF). ANALYTICAL APPROACH: Multivariable linear regression and linear mixed-effects models. RESULTS: Among 491 AASK participants (mean age 54 years; 37% women; mean glomerular filtration rate, 45 mL/min/1.73 m2), 367 cross-sectional associations between metabolites and inflammatory proteins were significant after correction for multiple comparisons. The direction of association was mostly positive for TNFR1 (97%), TNFR2 (97%), IL-8 (77%), and IL-10 (100%); negative for UMOD (80%) and EGF (97%); and variable for TNF-&#x237a;, IFN-&#x3b3;, and IL-6. Pathways were distinct for several inflammatory proteins (eg, tryptophan metabolism for TNFR2). Forty-five associations between metabolites and longitudinal change in inflammatory proteins were identified. Notable metabolites included tigylcarnitine and N 2,N 5-diacetylornithine, which were associated with 2-year increases in TNFR1 and/or TNFR2, and 1,5-anhydroglucitol, where lower levels were associated with decreases in UMOD. In ARIC (n = 3,773) and BKBC (n = 413), replication of cross-sectional associations was excellent for TNFR1 (ARIC 83%; BKBC 85%) and TNFR2 (ARIC 64%; BKBC 79%) but poor for IL-8 (ARIC 3%; BKBC 3%). LIMITATIONS: Metabolite data limited to baseline visit; potential for residual confounding. CONCLUSIONS: Using an untargeted approach, multiple metabolites were cross-sectionally and longitudinally associated with inflammatory proteins in persons with chronic kidney disease.

Chronic kidney disease↗
PubMed2026

Immunological, Inflammatory, and Microbiota Determinants of Carpal Tunnel Syndrome: Evidence from Mendelian Randomization.

INTRODUCTION: Carpal Tunnel Syndrome (CTS) is a common peripheral neuropathy, and immune dysregulation and microbial dysbiosis are believed to play a role in its development. However, the cause-and-effect relationships have yet to be clarified. METHODS: Using publicly available Genome-Wide Association Study (GWAS), there are 731 immune cell phenotypes, 91 inflammatory proteins, 150 skin microbiota taxon, and 473 gut microbiota taxon based on two-sample Mendelian Randomization (MR) analysis to test whether there is a causal relationship between them and CTS. The results from the study were shown to have some degree of stability as demonstrated by various sensitivity analyses, which included running heterogeneity tests, performing MR -PRESSO, and running MR-Egger regressions. On the other hand, reverse MR was performed to verify the direction of the association. In addition, a two-step MR mediation analysis was conducted to explore whether there was a mediation effect of gut microbiota and skin microbiota, respectively, of immune and inflammatory traits on CTS. RESULTS: 22 Immune cell traits, 4 Inflammatory proteins, 18 gut microbiota taxa, and 3 skin microbiota taxa are causally associated with CTS. Reverse MR suggested feedback effects of CTS on select immune traits and gut microbiota. Mediation analysis revealed 4 gut microbiota taxa that substantially mediated immune/inflammatory effects upon CTS, with mediation rates as high as 44%; however, skin microbiota did not demonstrate any mediation. DISCUSSION: The immune dysregulation, inflammation, and the gut microbiota that cause CTS are all revealed through this research. Mendelian randomization analysis suggests that traits and inflammatory proteins of immune cells directly increase the risk of CTS, and certain types of gut microbes partially mediate these effects. Therefore, the results show a central role of the immune-gut axis in CTS pathogenesis, and suggest a systemic, rather than a local, immune-microbial interaction in disease development. CONCLUSION: We provided the first causal evidence that immune cells, inflammatory proteins, and CTS risk are causally associated with some specific taxa of gut microbiota. This contributes to a better understanding of the immune-microbiome interactions in the process of occurrence and development of CTS, and also provides theoretical support for precision prevention and treatment.

Humans↗
PubMed1976

A method for determining plasma proteins in inflammatory exudate absorbed by Sephadex.

Dry cross-linked dextran (Sephadex pharmaceutical grade, Debrisan) was applied to weeping sores. After some exudate had been absorbed the gels were removed. The amount of exudate was determined by isotope dilution techniques. The accuracy of the method was tested by determination of plasma proteins in samples of diluted serum containing known concentrations of some plasma proteins. The method seems suitable for determining various high and low molecular weight constituents of exudates.

Absorption↗
PubMed1976

The role of the acute phase reaction in inflammation.

Inflammation and injury to tissue results in a variety of local and systemic events, however although the local events of oedema formation and cellular infiltration have received considerably more attention the systemic response to inflammation is no less profound. The particular systemic event which forms the substance of this communication is the change in the circulating levels of plasma proteins which occurs after inflammatory injury, and the manner in which these changes in plasma concentration are controlled by changes in plasma concentration are controlled by changes in the rate of synthesis. A discussion of the role of the liver in controlling inflammatory events, in relation to the synthesis of an anti-inflammatory protein has been given; the present work is an extension of this and describes the changes in concentration and synthesis rate of albumin, fibrinogen and alpha1 acid glycoprotein during adjuvant arthritis in the rat. The changes which occur are regulated at the liver by alteration of the rate of synthesis of the individual protein. For example albumin at the height of adjuvant arthritis falls to a third of its normal plasma level whereas the level of alpha1 acid glycoprotein increases up to twenty-fold; these changes are reflected by similar changes in their synthesis rate by the liver. The effect of the fall in albumin concentration on the plasma binding of anti-inflammatory drugs (and their toxicity) in relation to these findings will be discussed along with the biological role of the acute phase plasma proteins and hence the influence of the liver in the response to injury.

Animals↗
PubMed2026

Proteomics Analysis of Plasma for Risk of Sepsis: Findings from the Atherosclerosis Risk in Communities Study.

BACKGROUND: Sepsis is a life-threatening complication of infection with high mortality. A high-throughput analysis of circulating blood proteins may provide mechanistic insight and potent therapeutic targets for the prevention of sepsis. METHODS: We used multivariable Cox regression analysis to examine the association of 4955 plasma proteins, measured by SomaScan, with the risk of incident sepsis among 11 065 participants of the Atherosclerosis Risk in Communities (ARIC) Study (visit 3 in 1993 to 1995; mean age, 60.1 years, 54.4% female, 21.0% Black). Proteins (false discovery rate [FDR] of P < 0.05) discovered at visit 3 were replicated using data at visit 5 (n = 4869 in 2011 to 2013: mean age, 75.5 years) and in the Cardiovascular Health Study (CHS) (n = 3512 in 1992 to 1993; mean age, 74.5 years). Canonical pathways were identified by enrichment analyses. RESULTS: At ARIC visit three, 669 proteins were associated with the risk of sepsis; 175 were replicated at visit 5. Of these, 90 were validated in the CHS. The top 20 proteins ranked by P value were relevant to acute inflammatory signaling in innate immunity. Pathway analyses implicated activation of pro-inflammatory pathways (e.g., cytokine storm signaling) as well as inhibition of anti-inflammatory pathways (e.g., liver X receptor/retinoid X receptor [LXR/RXR] activation), which also play relevant roles in lipid metabolism. CONCLUSIONS: In this analysis, levels of acute inflammatory proteins measured during routine visits were associated with the subsequent incidence of sepsis. An increased risk of sepsis associated with the inhibition of anti-inflammatory pathways, such as LXR/RXR warrants further mechanistic investigation.

Humans↗
PubMed2026

Genetic and molecular evidence linking CTSH to Alzheimer's disease pathophysiology.

INTRODUCTION: Lysosomal dysfunction contributes to Alzheimer's disease (AD) by impairing protein clearance and promoting neuroinflammation. Cathepsin H (CTSH), a lysosomal protease, recently emerged as a protective AD locus. We investigated how CTSH is regulated and how it influences early AD pathophysiology. METHODS: We analyzed genomic, transcriptomic, and proteomic data from cerebrospinal fluid (CSF) and brain tissue across three independent clinical and post mortem cohorts to assess CTSH regulation, expression, and disease associations. RESULTS: The coding variant rs2289702 acts as a cis-regulatory variant, altering CTSH mRNA and protein levels. The T allele associates with better cognition and reduced amyloid plaque burden. CSF CTSH correlates with total tau, phosphorylated tau181, neuronal markers, and multiple glial and complement-related inflammatory proteins. DISCUSSION: CTSH tracks early neurodegenerative, synaptic, and inflammatory changes, and co-expression analyses link it to broader immune-metabolic pathways. The findings position CTSH as a genetically regulated contributor to AD pathophysiology.

Humans↗
PubMed2025

HEPARIN AND DNase I TREAT MYOCARDIAL INJURY IN SEPTIC MICE.

Background: Sepsis is a life-threatening clinical condition often seen in intensive care units, leading to multi-organ dysfunction. Myocardial injury is a prevalent complication, significantly increasing mortality among sepsis patients. Although heparin is used in sepsis management, its specific effects on myocardial injury and the role of neutrophil extracellular traps (NETs) in this context remain insufficiently understood. Aim: This study investigates the role of unfractionated heparin (UFH) combined with DNase I in reducing myocardial injury in a septic mouse model. Methods: A cecal ligation and puncture (CLP)-induced sepsis model was established in C57BL/6 mice to study myocardial injury. The experimental groups included treatments with UFH, UFH with DNase I, and NETs introduction. Myocardial injury was assessed using hematoxylin and eosin staining, enzyme linked immunosorbent assay for injury markers (creatine kinase MB [CK-MB] and lactate dehydrogenase [LDH]), and Western blotting for inflammatory proteins (TNF-&#x3b1; and IL-6). Differential proteomic analysis using data independent acquisition mass spectrometry and pathway enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) were conducted to identify molecular pathways and key proteins affected by the treatments. Results: Single UFH treatment increased the formation of NETs, upregulated TNF-&#x3b1; and IL-6, and increased CK-MB and LDH, worsening myocardial injury. The combination of UFH and DNase I significantly reduced myocardial injury, suppressing NETs formation and inflammation. Proteomic analysis identified crucial pathways related to NETs, metabolism, and complement and coagulation cascades, with proteins Ccn1 and Tagln highlighted as potential therapeutic targets. Conclusion: UFH combined with DNase I effectively alleviates myocardial injury in septic mice by modulating NETs formation and associated inflammatory processes. This study may provide new insights and options for the early use of heparin in the treatment of septic patients, particularly in cases with a higher risk of myocardial injury.

Animals↗
PubMed2026

The alarmin interleukin-33 modulates platelet proteome, function, and biogenesis.

Platelets, traditionally recognized for their involvement in hemostasis and wound healing, also play a central role in immune regulation and inflammation. Their function and production adapt in response to inflammatory cues such as cytokines and danger-associated molecular patterns. Interleukin-33 (IL-33), an alarmin released during tissue damage, particularly in lung inflammation, has been implicated in influencing platelet biology, though its exact effects remain poorly understood. To clarify IL-33's role, we examined its impact on platelet production, proteome, adhesion, secretion, and aggregation using platelets from IL-33-deficient (IL-33 knockout [IL-33KO]) mice and IL-33 stimulation in vivo. Our results reveal that although platelets themselves do not express IL-33, platelets isolated from IL-33KO mice display altered proteomic signatures and reduced adhesion to fibrinogen, podoplanin, and laminin, alongside impaired thrombus formation under shear stress. IL-33 administration in vivo led to proteomic remodeling characterized by increased expression of inflammatory proteins, as well as changes in platelet morphology, including increased size, typically associated with de novo production. Using lung intravital microscopy, we visualized platelet fragmentation within the lung vasculature in real time, and observed enhanced fragmentation following IL-33 stimulation. Interestingly, ST2, the receptor for IL-33, is expressed in subsets of mouse and human megakaryocytes and hematopoietic progenitors, particularly those involved in a noncanonical pathway of thrombopoiesis that enables the rapid replenishment of platelets during inflammation, infection, and aging. Together, these findings identify IL-33 as a pivotal regulator of platelet function and production, linking inflammatory signaling to the dynamic regulation of thrombopoiesis.

Interleukin-33↗