Inflammation最新文献

Following peripheral nerve injury (PNI), the ferroptosis-inflammation axis restricts the neural repair process. As a critical neuroregenerative factor, the mechanism by which CXCL12 promotes nerve repair by regulating the ferroptosis-inflammation axis remains unclear. This study systematically investigated the mechanism of CXCL12 using a combination of clinical samples, as well as cellular and animal experimental models. Clinical data showed that CXCL12 levels in the serum of PNI patients were significantly elevated at 72 hours post-surgery, suggesting its potential involvement in the early regulatory process following nerve injury. In an LPS-induced Schwann cell (SC) injury model, CXCL12 effectively inhibited the occurrence of ferroptosis by activating the ERK/Nrf2 signaling pathway, which led to reduced cellular Fe²⁺ accumulation, downregulation of ACSL4, and upregulation of GPX4 and FSP1 expression. Further investigation revealed that the alleviation of cellular ferroptosis was accompanied by a decrease in NF-κB pathway activity, characterized by reduced levels of p-NF-κB and p-IκBα, as well as decreased secretion of TNF-α and IL-1β, indicating that CXCL12 possesses anti-inflammatory effects. Rescue experiments demonstrated that the ERK inhibitor U0126 partially reversed the anti-ferroptotic effect of CXCL12. Iron overload experiments (FAC) weakened the anti-inflammatory effect of CXCL12, whereas Ferrostatin-1 mimicked its anti-inflammatory action, suggesting that ferroptosis plays a pivotal role in the anti-inflammatory effects of CXCL12. Additionally, overexpression of NF-κB also diminished the anti-inflammatory efficacy of CXCL12. Animal experiments further confirmed that CXCL12 improved the mitochondrial structure of nerve tissues following PNI, reduced the accumulation of Fe²⁺ and lipid peroxidation, and promoted axonal and myelin regeneration. In conclusion, CXCL12 inhibits SC ferroptosis and reduces intracellular Fe²⁺ accumulation via the ERK/Nrf2 pathway, thereby attenuating the NF-κB-mediated inflammatory response and promoting nerve repair after PNI.

Periodontitis is a chronic inflammatory disease affecting tooth-supporting tissues. Beyond microbial dysbiosis, host metabolic regulation plays a critical role. This study identified ornithine aminotransferase (OAT), a mitochondrial enzyme in amino acid metabolism, as associated with altered fibroblast phenotypes and metabolic profiles in periodontitis. Integrative genetic analysis showed a putative causal relationship between increased OAT expression and disease risk. Single-cell RNA-Seq revealed OAT enrichment in fibroblasts, especially in subsets with inflammatory and matrix-remodeling characteristics. In diseased tissues, OAT-positive fibroblasts exhibited heightened metabolic activity and acted as central nodes in intercellular communication with immune and endothelial cells. Pseudotime analysis indicated progressive downregulation of OAT during fibroblast differentiation. OAT expression correlated with activation of arginine and proline metabolism, implicating a role in sustaining inflammation and matrix degradation. These results suggest that OAT contributes to periodontal tissue damage and may serve as a therapeutic target.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Despite advances in understanding its pathogenesis, the role of epigenetic regulation and non-coding RNA networks remains inadequately explored. This study investigates the involvement of N6-methyladenosine (m6A) modification and circular RNA (circRNA), specifically circINTS4, in RA.

Methods: We conducted a bibliometric analysis to map research trends in m6A and miR-146 family studies in RA. Whole-transcriptome sequencing was performed on synovial tissue from RA patients and healthy controls (HCs) to identify differentially expressed circRNAs. miRNA expression was profiled using publicly available datasets. The role of METTL3 in regulating circINTS4 was examined through loss-of-function experiments in RA fibroblast-like synoviocytes (RA-FLS). A dual-luciferase reporter assay validated the direct interaction between circINTS4 and miR-146b-3p. Functional assays in RA-FLS and in vivo models assessed the impact of circINTS4 depletion on disease progression.

Results: circINTS4 was the most significantly downregulated circRNA in RA, and miR-146b-3p was the most upregulated miRNA in RA patients. METTL3 depletion in RA-FLS reduced global m6A methylation and decreased m6A enrichment on circINTS4, leading to increased circINTS4 expression and decreased miR-146b-3p levels. Clinical analysis revealed an inverse relationship between circINTS4 and miR-146b-3p expression. Functionally, circINTS4 served as a sponge for miR-146b-3p, with its depletion enhancing RA-FLS proliferation, migration, and resistance to apoptosis. In vivo, circINTS4 knockdown exacerbated synovial inflammation and elevated pro-inflammatory cytokine levels in a rat model of RA.

Conclusion: Our findings reveal that METTL3-mediated m6A modification regulates the circINTS4/miR-146b-3p axis, modulating RA-FLS pathogenicity and inflammatory responses. CircINTS4 acts as a molecular sponge for miR-146b-3p and serves as a promising biomarker for RA disease severity. This study provides new insights into the role of m6A methylation and circRNA-miRNA networks in RA, highlighting their potential as diagnostic and therapeutic targets.