Inflammation Research最新文献

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.

Systemic sclerosis is an autoimmune connective tissue disease of unknown cause and diverse clinical manifestations. Vasospastic episodes (Raynaud's phenomenon), often triggered by cold or stress, typically appear at disease onset. Cytokines, particularly TGF-β, act in the inflammatory and hypoxic microenvironment to drive fibrosis, which predominantly develops at inflammatory sites. Several cell types contribute to disease pathogenesis and fibrosis, including vascular endothelial cells, vascular smooth muscle cells, and fibroblasts in the extracellular matrix. Multiple signaling pathways are activated in these cells and promote disease progression. Endothelial and vascular smooth muscle cells respond to diverse ligands through pathways such as AKT, MAPK, and GPCR signaling, which promote fibrosis progression in the profibrotic and proinflammatory milieu. Cytokines are also important mediators of inflammation and fibrosis, particularly by acting on activated monocytes in the ECM and guiding them toward M1 or M2 macrophage polarization. In the early inflammatory stage, M1 macrophages predominate, while the fibrotic stage is characterized by increased M2 macrophage presence. ECM accumulation, resulting from TGF-β signaling in fibroblasts, provides integrins with ligands and promotes enhanced adhesion and migration of these cells. TGF-β, on the other hand, can transactivate the Ras pathway, promoting myofibroblast differentiation and enhancing pro-fibrotic effects.

Objective and design: Astilbin (ATB) is a newly discovered natural compound with anti-inflammatory and immunomodulatory effects. However, its effects and underlying mechanisms in acute lung injury (ALI) remain unclear.

Material or subjects: An ALI model was established by intratracheal injection of lipopolysaccharide (LPS) into the trachea of C57BL/6 mice. In vitro, MLE-12 cells were stimulated with LPS. ATB was administered as a pretreatment to C57BL/6 mice and MLE-12 cells.

Results: ATB significantly alleviated ALI and suppressed the inflammatory response induced by LPS. Further data suggested that ATB inhibited LPS-induced ferroptosis in epithelial cells by increasing GPX4 and xCT expression. Moreover, ATB promoted NRF2 nuclear translocation in the LPS-treated group, while NRF2 inhibition significantly reversed the protective effects of ATB on ferroptosis and inflammation. NRF2 knockout in vivo abolished the protective effects of ATB against ALI and epithelial cell ferroptosis. Mechanistically, ATB increased NRF2 activity by binding to the Val608 amino acid of NRF2. The effect of ATB in improving ALI and ferroptosis was significantly reduced in NRF2 Val608 mutant mice.

Conclusion: ATB mitigated ALI by suppressing epithelial cell ferroptosis and activating the NRF2 pathway via binding to Val608 of NRF2.

Background: Clopidogrel resistance remains a significant clinical challenge in coronary artery disease (CAD), with traditional explanations focusing on CYP450 polymorphisms. However, emerging evidence highlights the critical role of inflammation and angiogenesis in modulating platelet reactivity and clopidogrel responsiveness. Genetic variants in these pathways may represent under recognized determinants of treatment failure. This pilot study investigated the association between single nucleotide polymorphisms (SNPs) in inflammation- (CCR2, CCL5, CCL2) and angiogenesis-related (KDR, VEGFA) genes and clopidogrel resistance.

Methods: In a cross-sectional study of 135 Tunisian CAD patients on dual antiplatelet therapy, clopidogrel response was assessed using VerifyNow P2Y12 assay (resistance defined as PRU  ≥  208). Nine SNPs were genotyped via PCR-RFLP. Associations were evaluated using logistic regression, adjusting for covariates.

Results: The CCL5 rs2280789-C allele conferred a 3.4-fold increased resistance risk (OR = 3.40 (1.54-7.48), p =  0.002), while the CCR2 rs1799864-A allele was protective (OR =  0.30 (0.10-0.84), p =  0.02). The KDR rs1870377-AA genotype tripled resistance odds (OR =  3.05 (1.05-8.83), p =  0.04). A polygenic model revealed synergistic effects: 53% of non-responders carried  ≥ 2 risk genotypes (CCR2-GG, CCL5-TC, KDR-AA) vs. 15% of responders (OR = 6.51 (2.86-14.83), p < 0.001). No associations were found for VEGFA or CCL2 SNPs.

Conclusion: Beyond CYP450-mediated metabolism, clopidogrel resistance is driven by immuno-vascular mechanisms involving CCL5-mediated thrombo-inflammation, CCR2-dependent monocyte recruitment, and VEGFR2-linked endothelial dysfunction. These findings advocate for precision antiplatelet strategies integrating inflammatory and angiogenic pathways to optimize therapy.

Objective: The aim of this study was to investigate whether antigen-specific reduced IgG inhibits mast cell activation evoked by the aggregation of the high-affinity IgE receptor (FcεRI) in a manner similar to intact IgG.

Materials: Rat basophilic leukemia (RBL-2H3) cells are used for a mast cell model.

Treatment: Monovalent mouse anti-trinitrophenyl (TNP) IgG1 (75 kDa) was prepared by reducing the disulfide bond between the heavy chains using cysteamine hydrochloride. IgE-sensitized RBL-2H3 cells were stimulated with TNP-OVA, and reduced IgG1 was added 5 min after stimulation.

Methods: Degranulation and IL-4 secretion were measured 30 min and 3 h after TNP-OVA stimulation by β-hexosaminidase assay and ELISA, respectively. The intracellular distribution of SH2-containing inositol 5'-phosphatase 1 (SHIP1) was determined using immunostaining. Group differences were analyzed using the Tukey-Kramer test.

Results: Reduced IgG1 significantly inhibited degranulation and IL-4 secretion in antigen-stimulated RBL-2H3 cells to an extent similar to intact IgG1. Intracellular SHIP1 localized to the plasma membrane 5 min after the addition of reduced IgG1, mirroring the effect of intact IgG1.

Conclusions: These results suggest that antigen-specific reduced IgG1 (monovalent) inhibits antigen-induced mast cell activation by activating SHIP1 through co-ligation of FcεRI and the low-affinity IgG receptor (FcγRIIB).