Inflammation Research最新文献

Background: Periodontitis has been associated with an increased risk of atherosclerotic cardiovascular disease; however, its association with subclinical myocardial injury remains scarce. The purpose of this study was to investigate the association between periodontitis, cardiac biomarkers of subclinical myocardial injury, and cardiovascular mortality in the general U.S.

Population:

Methods: We analyzed data from 9202 participants initially free of cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey. The grade of periodontitis was categorized into normal, mild, and moderate-severe. Survey-weighted multiple linear regression model assessed the association between periodontitis and cardiac biomarkers, including high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Survey-weighted multiple Cox regression model was utilized to estimate the association between periodontitis and cardiovascular disease mortality.

Results: The mean age of participants was 40.65 ± 0.32 years, with 48.44% being men. The individuals with mild and moderate-severe periodontitis had significantly elevated hs-cTn and NT-proBNP, which indicated impaired cardiac structure and function, compared with non-periodontitis individuals. After controlling confounding covariates, moderate-severe periodontitis was significantly correlated with elevated hs-cTnT and NT-proBNP (β coefficients: 0.055, 95% CI 0.004 to 0.106; β coefficients: 0.188, 95% CI 0.077 to 0.300, respectively). Sensitivity analysis and subgroup analysis further verified the robustness of the results. Over a 17.5-year follow-up period, individuals with moderate-to-severe periodontitis exhibited a 44.9% higher risk of cardiovascular mortality compared to those without periodontitis (hazard ratio: 1.449, 95% CI: 1.027 to 2.044).

Conclusion: In individuals without established cardiovascular disease, moderate-severe periodontitis was associated with higher concentrations of hs-cTn and NT-proBNP, as well as an increased risk of cardiovascular mortality. These results emphasize the importance of maintaining optimal oral health.

Background: Psoriatic disease (PsD) is a chronic systemic inflammatory condition associated with significant cardiometabolic comorbidities, including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular (CV) disease. These comorbidities are interlinked via shared immunopathogenic mechanisms, notably chronic low-grade inflammation driven by Th1/Th17 cytokines such as TNF, IL-6, and IL-17. Obesity, in particular, exacerbates PsD severity and treatment resistance, underscoring the need for integrated therapeutic strategies. This scoping review investigates the biological rationale and evidence for the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in PsD.

Findings: Originally developed for T2DM, GLP-1RAs have demonstrated efficacy in reducing weight and improving glycemic control and CV outcomes. Evidence also suggests immunomodulatory properties through modulation of key inflammatory pathways and immune cell activity. We examined studies addressing: (1) the impact of obesity, T2DM, and CV disease on PsD; (2) outcomes of GLP-1RAs in these comorbidities; and (3) their potential in related rheumatologic and dermatologic diseases. GLP-1RAs show promise in reducing PsD burden by improving metabolic parameters and reducing systemic inflammation. Early clinical and preclinical data suggest benefits also in rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa.

Implications: GLP-1RAs represent a novel, multifaceted therapeutic option in PsD, targeting both metabolic and inflammatory components. Further clinical trials are warranted to define their role in comprehensive PsD management and validate their disease-modifying potential.

Wound healing is a complex and tightly controlled physiological process that involves various cell types, among which macrophages play a critical role in tissue repair and regeneration. Transcription regulators influence gene expression in macrophages at several phases of wound healing, such as hemostasis, inflammation, proliferation, and remodeling. This article explores the transcription factors that regulate the activity of macrophages during wound healing and help in ECM remodeling. Understanding how these transcription regulators coordinate macrophage actions in response to cellular and molecular stimuli is essential for determining the process behind acute and chronic healing. This review highlights the therapeutic interventions through modulating transcriptional activity to improve wound healing and resolve fibrosis in chronic wounds. Furthermore, this review also explores the roles of transcription factors in macrophages, suggesting valuable insights into innovative strategies to improve tissue regeneration in chronic or pathological conditions.

Background: Lysophosphatidyl choline acyltransferase 3 (LPCAT3) is crucially involved in the remodeling of phospholipids in the membranes through incorporation of arachidonic acid (ARA; 20:4). The ARA-derived eicosanoids aggravate leukocyte adhesion, inflammation, vascular dysfunction, thrombosis, and atherogenesis. This study found that LPCAT3 modulates lipid rafts and contributes to the raft assembly/organization essential for cytokine signaling.

Methods: RNAi-dependent silencing of LPCAT3 in the endothelial cells. EPA and DHA enrichment in the cells. Lipid raft isolation and analysis of proinflammatory signaling molecules. Diet-induced atherosclerosis in the mice. LPCAT3 siRNA lipid nanoparticles/ EPA, DHA therapy.

Results: RNAi-dependent silencing of LPCAT3 inhibits TNFα-induced translocation & ubiquitination of TNFR1-signaling complex into the lipid rafts. This is associated with the attenuated NF-κB activation, synthesis of cell-adhesion molecules, cytokines, leukocyte adhesion, vascular permeability and endothelial dysfunction. Intriguingly, LPCAT3 inhibition resulted in significantly greater accretion of EPA and DHA in the PC and PE at the expense of ARA, and potentially decreased the ARA-derived eicosanoids in the vascular endothelium. Therapeutic administration of LPCAT3 siRNA-lipid nanoparticles in the high fat fed- mice markedly lowered the plasma glucose, insulin, proinflammatory cytokines, eicosanoids, and attenuated the plaque formation in the aorta. Co-treatment of LPCAT3 siRNA-lipid nanoparticles with EPA/DHA significantly elevated the accretion of EPA/DHA levels in the heart tissues and nullified the plaque development in the mice.

Conclusions: Our data revealed that LPCAT3-dependent remodeling of lipid rafts is essential for the TNF-induced signal transduction, NF-kB activation, and vascular inflammation. Administration of LPCAT3 siRNA-lipid nanoparticles and EPA/DHA is an effective strategy to combat atherosclerosis.

Background: Microglia, the primary immune cells of the central nervous system, play a pivotal role in orchestrating neuroinflammatory responses and maintaining neural homeostasis. Post-translational modifications (PTMs) are critical regulators of microglial inflammatory activation, phagocytic capacity, and crosstalk with other neural cells.

Findings: This review highlights seven PTMs-phosphorylation, acetylation, methylation, ubiquitination, succinylation, SUMOylation, and lactylation-that are closely linked to the modulation of microglial inflammation. We discuss how these modifications shape microglial phenotypes during central nervous system diseases, particularly in the context of neuroinflammation, and explore their potential as therapeutic targets for inflammation-driven neuropathologies.

Implications: Understanding the regulatory landscape of PTMs provides valuable insights into microglial biology and the mechanisms underlying neuroinflammatory disorders. This review aims to summarize current evidence and offer a concise overview that may assist future research on PTM-mediated regulation of microglial function and its relevance to neurological diseases.

Objective: The dual specificity phosphatase 6 (DUSP6) was recently implicated in autoimmune arthritis pathogenesis. However, it remains unclear which cell mediates its pathogenic activity in a mouse model of rheumatoid arthritis (RA).

Methods: Bone marrow (BM) CD11b + Gr1 + cells were isolated from DUSP6 +/+ mice and transferred into DUSP6 -/- recipients. Six weeks later mice were administered the KRN serum to induce arthritis (KSIA), and analyzed for arthritis severity clinical scores. The same strategy was used in the opposite direction with cells from DUSP6-/- cells transferred in DUSP6 +/+ mice. BM CD11b + Gr1 + cells from DUSP6 +/+ and DUSP6 -/ - were stimulated with PMA and used for RNA sequencing, and also used for real-time measurements of mitochondrial respiration with the Seahorse XF Analyzer.

Results: Transfer of CD11 + Gr1 + cells DUSP6^+/+ mice into DUSP6^-/- mice reversed the arthritis protection observed in the knockout mice, and developed severe disease. Transfer of cells from DUSP6^-/- into DUSP6^+/+ were not protective and mice still developed severe disease. Cells from DUSP6 +/+ mice had a significantly higher oxidative burst, and higher glycolysis, compared with reduced levels in DUSP6-/-. RNA sequencing analyses revealed an enrichment for differentially expressed genes implicated in RA, MAPK signaling, leukocyte differentiation and neutrophil degranulation, among others.

Conclusion: We describe a new arthritogenic role for DUSP6, which is mediated by CD11b + Gr1 + cells and their glycolytic activity and oxidative burst. Our findings also implicate these myeloid cells in arthritis pathogenesis and raise the possibility that DUSP6 may be a good target for the development of new therapies for RA.

Objective: Regarding the participation of RUNX1 in lung cancer, we investigated its mechanism in regulating M2 polarization of tumor-associated macrophages in lung cancer.

Methods: The extracted bone marrow cells were differentiated into macrophages (BMDMs), followed by tumor-conditioned medium (CM) stimulation to simulate the impact of tumor cells on macrophages in vivo, and treatment with RUNX1 shRNA, or pCDNA3.1-ACP5 and SIS3. Macrophage polarization and cytokine secretion were assessed by flow cytometry and ELISA, followed by evaluations of RUNX1, ACP5, p-β-catenin, β-catenin and p-SMAD3 levels. The ACP5-β-catenin interaction was detected by Co-IP. BMDMs were co-cultured with Lewis lung carcinoma cells using Transwell. The malignant behaviors of cells were assessed by CCK-8 and Transwell assays. In vivo experiments were conducted to verify roles of RUNX1.

Results: Tumor-CM stimulated BMDM M2 polarization. RUNX1 was up-regulated in tumor-CM-stimulated macrophages and M2-type BMDMs, and was poorly expressed in M1-type BMDMs. RUNX1 knockdown induced M1 marker expression and reduced M2 marker expression, and repressed non-small cell lung cancer (NSCLC) cell malignant behaviors. The effects of RUNX1 silencing were partly abrogated by ACP5 overexpression. ACP5 interacted with β-catenin to promote SMAD3 phosphorylation. Downregulation of SMAD3 phosphorylation partially reversed tumor-CM-promoted BMDM M2 polarization and NSCLC cell malignant behaviors. RUNX1 promoted M2 polarization and NSCLC cell malignant behaviors by promoting ACP5-mediated SMAD3 phosphorylation. RUNX1 knockdown inhibited M2 polarization in LLC mice to suppress tumor growth in vivo.

Conclusion: RUNX1 promoted BMDM M2 polarization by facilitating the interaction between ACP5 and β-catenin to elevate SMAD3 phosphorylation, thus promoting NSCLC progression.

Objective: This study investigates the dual regulatory role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in macrophage polarization and its therapeutic potential for mitigating myocardial ischemia/reperfusion injury (MI/RI).

Methods: By integrating in vivo murine myocardial MI/RI models with macrophage-specific genetic manipulation and multi-omics analyses, including transcriptomics, proteomics, and energy metabolomics, we comprehensively investigated the cardio-protective effects, immune regulation, and potential mechanism of PGC1α. Mechanistic validations were performed using macrophage hypoxia/reoxygenation models combined with gain- and loss-of-function experiments to elucidate the molecular interactions within the PGC1α-mediated signaling network.

Results: PGC1α emerged as a potential regulator of macrophage polarization through coordinated metabolic and protein regulation in MI/RI. It suppresses TLR4/NF-κB-driven inflammation via two prominent parallel pathways: (1) Metabolic control through SUCLG1/succinyl-CoA synthetase-mediated succinate generation; (2) negatively regulates protein by TRAF5 mRNA expression inhibition. This dual-axis regulation effectively dampens M1 macrophage polarization and pro-inflammatory cytokine storms. Furthermore, macrophage-specific PGC1α activation demonstrated cardio-protective effects by preserving cardiac function and reducing cardiomyocyte apoptosis.

Conclusion: Our findings established PGC1α as a potential regulator of macrophage polarization in MI/RI, bridging mitochondrial energy metabolism and protein expression with immune responses. The PGC1α-SUCLG1/succinate axis and PGC1α-TRAF5 axis unveil therapeutic targets and potential mechanisms for modulating inflammation in MI/RI. Future studies should focus on translating these mechanisms into clinical interventions through pharmacological PGC1α activation.

Introduction: The clinical relevance of circulating inflammatory proteins in Immunoglobulin A nephropathy (IgAN) remains incompletely defined. We examined whether serum inflammatory proteins-particularly tumor necrosis factor (TNF) receptor-related markers-track with disease severity and progression in IgAN.

Methods: We enrolled Japanese subjects undergoing native kidney biopsy with newly diagnosed IgAN (n = 134); disease controls with membranous nephropathy (n = 24), minimal change disease (n = 45), or lupus nephritis (n = 23); and healthy controls (n = 88). We measured 10 serum inflammatory proteins before renal biopsy and evaluated their levels in different glomerulonephritis. Additionally, we assessed associations between these proteins and clinical outcomes, including kidney function and histological changes in IgAN.

Results: Inflammatory proteins, especially TNF-R1, TNF-R2, TNF-R3, TNF-R7, and TNF-R27, were elevated in patients with IgAN and were associated with the severity of tubulointerstitial lesions. Among disease controls, membranous nephropathy and lupus nephritis also showed elevated TNF-receptor-related proteins, whereas minimal change disease did not. TNF-R7 showed a significant early increase, suggesting possible involvement in IgAN pathogenesis. Multivariable analysis indicated these proteins could predict kidney function decline.

Conclusions: Specific circulating inflammatory proteins, particularly in the TNF receptor pathway, reflect disease activity and structural injury in IgAN and may help identify patients at higher risk of progression.