Inflammation Research最新文献

Background: Immune-mediated inflammatory diseases (IMIDs) are chronic disorders involving multiple organs and driven by shared pathogenic pathways. Current therapeutic approaches, such as disease-modifying anti-rheumatic drugs (DMARDs) and biologics, are limited by infection risks, poor tissue specificity, and suboptimal long-term efficacy, underscoring the need for novel therapies. Nanozymes, nanomaterials with enzymatic activities, have garnered considerable interest for treating IMIDs due to their potential to counteract oxidative stress. Nevertheless, a systematic assessment of their therapeutic applications, mechanisms, and clinical translation challenges in IMIDs remains lacking.

Findings: Given the critical pathogenic role of reactive oxygen species (ROS) in IMIDs, nanozymes, particularly those with oxidoreductase activity, have demonstrated significant therapeutic potential. They modulate ROS levels, restore immune homeostasis, and remodel the local inflammatory microenvironment, either as monotherapy or in combination with conventional agents. To overcome challenges such as biosafety, off-target effects, and clinical translatability, strategies successfully explored in other diseases, such as biodegradable or organic-inorganic hybrid nanozymes, pH-responsive targeting designs, erythrocyte membrane coatings, and ROS-responsive carriers, may be adapted to enhance tissue specificity and safety in IMID treatment. Further investigation is warranted to adapt and optimize these strategies for effective and safe nanozyme-based therapy in IMIDs.

Conclusion: This review synthesizes current evidence to summarize the therapeutic potential and underlying mechanisms of nanozymes in IMIDs, while highlighting key challenges and future directions to guide the development and clinical translation of nanozyme-based therapies.

Objective and design: N6-methyladenosine (m⁶A), the most prevalent RNA modification, plays a crucial role in regulating macrophage homeostasis and intestinal immunity, although its mechanism remains largely unknown. A link between increased methyltransferase-like 3 (METTL3) expression in macrophages and intestinal inflammation has been confirmed. Herein, we sought to determine the role of METTL3-mediated macrophage activation in colitis.

Methods: The dextran sulfate sodium (DSS)-induced experimental colitis model was established. Conditional knockout of METTL3 in myeloid cells mice (Mettl3^fl/flLyz2^Cre) and myeloid cells-specific deletion of IRAKM mice (Irakm^fl/flLyz2^Cre) were generated, respectively. The severity of colitis was measured using the disease activity index, colon length, and histopathological staining. Various techniques such as flow cytometry, western blot, quantitative PCR, and RNA-seq analysis were employed to assess polarization and the expression of inflammatory cytokines.

Results: Conditional knockout of Mettl3 in myeloid cells attenuated intestinal inflammation in experimental colitis. In vivo and in vitro studies confirmed that Mettl3 deletion skewed macrophages towards M2 activation. Mechanistically, Irakm, a negative regulator of TLR4 signaling, was identified as a target of METTL3-mediated m⁶A modification. METTL3 deficiency led to a higher level of IRAKM, which ultimately suppressed TLR signaling-mediated macrophage activation. Myeloid cells-specific deletion of Irakm mice were more susceptible to DSS-induced colitis than were wild-type mice. Colon-infiltrating M1 macrophages from Irakm^fl/flLyz2^Cre mice dramatically increased compared with those from their counterpart Irakm^fl/fl mice. Additionally, deletion of IRAKM in bone marrow-derived macrophages (BMDMs) induced NF-κB activation and facilitated M1 polarization.

Conclusion: Our study highlights the role of METTL3-IRAKM signaling in macrophage polarization and intestinal inflammation, providing a potential therapeutic target for the treatment of colitis.

Background: Sepsis-associated encephalopathy (SAE) is a common and severe neurological complication of sepsis that markedly worsens long-term outcomes. Growing evidence suggest that metabolic reprogramming in microglia is a major driver of neuroinflammation in SAE; however, the molecular mechanisms that altered metabolism and inflammatory responses remain unclear.

Methods: Transcriptomic data from public hippocampal datasets of SAE mice were analyzed to identify potential molecular drivers. We established a CLP-induced SAE model and performed AAV-mediated knockdown. For in vitro validation, BV2 microglia were treated with LPS to simulate neuroinflammation. Mechanistic validation was conducted using both genetic and pharmacological interventions. Cellular metabolism was examined through extracellular flux analysis and metabolite detection. Inflammatory responses were evaluated by cytokine profiling, and disease phenotypes were assessed using behavioral tests and histological analyses.

Results: S100A8 was markedly upregulated in activated microglia during SAE. Its knockdown reduced microglial activation, protected hippocampal neurons, and improved cognitive performance. Transcriptomic profiling identified PFKFB3 as a downstream glycolytic target of S100A8. Mechanistically, S100A8 activated the PI3K/AKT/HIF-1α signaling cascade, thereby upregulating PFKFB3 and promoting glycolytic reprogramming and cytokine release. Functionally, S100A8 knockdown lowered lactate production and LDH activity, while reducing TNF-α, IL-6, and IL-1β secretion. Rescue experiments confirmed that PFKFB3 mediates the glycolytic and pro-inflammatory effects of S100A8.

Conclusions: This study demonstrates that S100A8 exacerbates SAE-related neuroinflammation and cognitive impairment by driving microglial metabolic reprogramming toward glycolysis via the PI3K/AKT/HIF-1α-PFKFB3 pathway. These findings highlight a mechanistic link between S100A8 and microglial metabolic reprogramming and neuroinflammation, and suggest that S100A8 could be a promising target for therapeutic intervention in SAE.

Background: Sepsis-associated encephalopathy (SAE), a neurological complication of sepsis without direct CNS infection, currently lacks established pharmacological therapy. Key pathological features include excessive microglial activation and blood-brain barrier (BBB) disruption. Our prior work showed that recombinant Trichinella spiralis 53-kDa glycoprotein (rTsP53) modulates intestinal endothelial tight junctions in septic mice by downregulating inflammation.

Methods: We analyzed inflammatory factor levels and performed bioinformatics analysis on cerebrospinal fluid (CSF) from SAE patients. In a cecal ligation and puncture (CLP)-induced septic mouse model, we assessed brain inflammatory cytokines, BBB permeability, tight junction protein expression, microglial activation, and transcription factor p65 levels. Mice were prophylactically treated with rTsP53 prior to septic insult.

Results: CSF from SAE patients showed significantly elevated inflammatory factors and upregulated leukocyte migration/chemotaxis pathways. CLP-induced septic mice exhibited increased brain inflammatory cytokines, enhanced BBB permeability, reduced tight junction protein expression, microglial activation, and elevated p65. Prophylactic rTsP53 treatment decreased pro-inflammatory cytokines (IL-6, IL-17A) and p65, increased anti-inflammatory factors (IL-4, IL-13), and alleviated BBB damage.

Conclusion: Prophylactic rTsP53 mitigates sepsis-induced brain inflammation and BBB disruption in mice by modulating the microglial response. These findings provide preclinical evidence supporting the further exploration of rTsP53 as a potential preventive agent for SAE.

Objective and design: This study aimed to investigate the mechanism by which Caveolin-1 (Cav-1) deficiency leads to cardiac dysfunction, utilizing both in vivo and in vitro experimental models.

Material or subjects: Experiments used 43-52-week-old wild-type (WT) and Cav-1 knockout (Cav-1^-/-) mice (n=5 per group), and the H9C2 rat cardiomyocyte cell line.

Treatment: In vivo, Cav-1^-/-mice received rapamycin (0.25 mg/kg). In vitro, H9C2 cells underwent Cav-1 knockdown/overexpression and were treated with rapamycin (100 nM), chloroquine (20 µM), AMPK activator A-769662, adiponectin (APN, 5 µg/ml), or AdipoR1 overexpression.

Methods: Cardiac function was assessed by echocardiography (LVEF, LVFS). Protein expression was analyzed via western blotting and immunofluorescence. Autophagic flux was measured using mRFP-GFP-LC3B lentivirus. Apoptosis was evaluated by TUNEL staining and flow cytometry. Data are mean ± SD; statistical analysis used t-tests/ANOVA.

Results: Cav-1^-/- mice exhibited impaired cardiac function (LVEF: reduced vs. WT, p<0.05), suppressed autophagy, increased apoptosis, and elevated inflammation/fibrosis. In H9C2 cells, Cav-1 knockdown inhibited AMPK phosphorylation, activated mTOR, and repressed autophagy, effects reversed by Cav-1 overexpression or rapamycin/AMPK activation. Bioinformatic and immunofluorescence analyses identified AdipoR1 downregulation in Cav-1^-/- hearts; APN/AdipoR1 overexpression rescued autophagy and reduced apoptosis.

Conclusions: Cav-1 deficiency induces cardiac dysfunction by suppressing autophagy via the AdipoR1-AMPK-mTOR pathway, highlighting Cav-1 as a potential therapeutic target for cardiac dysfunction.

Objective: To characterize the longitudinal trajectories of multi-category biomarkers and evaluate their association with 21-day all-cause mortality in critically ill burn patients with sepsis.

Methods: In this retrospective single-center cohort study, we analyzed 943 adult burn patients with sepsis, defined per Sepsis-3.0 criteria. Serial measurements of 15 biomarkers across nutritional, immunoglobulin, lymphocyte subset, inflammatory, and other categories were collected over 21 days. We employed linear mixed-effects models (LME) to compare trajectories between survivors and non-survivors, Cox regression to assess associations with mortality, time-dependent ROC to evaluate predictive performance, and k-means clustering to identify patient phenotypes based on integrated ALB, IL-6, and IgG trajectories.

Results: The 21-day mortality was 17.92%. LME revealed significantly different trajectories for 11 biomarkers between survivors and non-survivors (P < 0.05). Univariate Cox analysis identified multiple significant biomarkers, with transferrin (HR = 0.985, P = 6.84 × 10⁻¹¹) and IgM (HR = 0.284, P = 1.24 × 10⁻⁵) as strong protective factors, and mitochondrial DNA (HR = 1.002, P = 1.89 × 10⁻⁹) as a risk factor. In multivariate analysis, only the Burn Index remained an independent risk factor (HR = 1.066, P < 0.001). Time-dependent ROC showed peak predictive accuracy at Day 7 (albumin AUC = 0.729). Clustering identified three distinct phenotypes-"Rapid Recovery" (mortality 5.2%), "Persistent Inflammatory & Catabolic" (mortality 38.0%), and "Intermediate" (mortality 18.7%; P < 0.001)-with starkly different biomarker trends and clinical profiles.

Conclusions: The dynamic patterns of multi-category biomarkers are strongly associated with short-term survival in burn sepsis. While burn severity is a dominant baseline risk factor, longitudinal trajectory analysis captures the essence of the host's recovery or failure, effectively stratifying patients into prognostically distinct subgroups. This trajectory-based phenotyping highlights the potential of monitoring the host response over time to improve risk assessment and guide personalized management.

Background: Erianin (Eri) has been known for its analgesic and antipyretic properties. This research focuses on impact of Eri on chondrocyte viability, inflammatory cytokine production, extracellular matrix (ECM) degradation, and ferroptosis, which are key factors in cartilage diseases.

Methods: The mouse model of osteoarthritis (OA) was induced by destabilization of medial meniscus (DMM). Chondrocytes were treated with different concentrations of Eri and exposed to IL-1β to simulate disease conditions. The chondrocytes were induced to undergo ferroptosis using erastin (Era), and ferroptosis was inhibited by Fer-1. This was done to form an intervention control group in combination with Era and to explore the synergistic effect. The effects of Eri on cell viability, proliferation, inflammatory responses, ECM degradation, and ferroptosis were assessed using CCK-8 analysis, EDU assay, Western blot, immunofluorescence, ROS staining, and flow cytometry. The Cellular Thermal Shift Assay (CETSA) was also employed to confirm the direct binding and thermal stability of GPX4 and STING in the presence of Eri.

Results: The findings indicate that Eri does not exhibit cytotoxic effects at certain concentrations and can actually enhance chondrocyte proliferation and viability. It also reduces the production of inflammatory cytokines and ECM degradation products, suggesting a protective role against cartilage damage. Furthermore, Eri was found to inhibit ferroptosis in chondrocytes, potentially through the activation of the GPX4/STING signaling pathway. Molecular docking combined with CETSA confirmed that Eri enhances the thermal stability of GPX4 and STING, indicating a stabilizing effect on this key enzyme. In the DMM mouse model, Eri significantly alleviated cartilage degeneration and improved chondrocyte function, as evidenced by reduced osteophyte formation and subchondral bone sclerosis. Eri can act independently or in combination with the ferroptosis inducer erastin (Era) and the ferroptosis inhibitor Ferrostatin-1 (Fer-1). By inhibiting lipid peroxidation, regulating cell proliferation and extracellular matrix degradation, it exerts an intervention effect on IL-1β-induced ferroptosis of chondrocytes. Moreover, when used in combination with Fer-1, it has a synergistic enhancing effect in reversing ferroptosis-related damage.

Conclusions: Eri demonstrates promising therapeutic potential in the treatment of OA by inhibiting chondrocyte ferroptosis and protecting against ECM degradation and inflammatory responses.

Objective: To develop an interpretable prognostic prediction model for autoimmune encephalitis (AE) using immunological indicators and to investigate the potential role of nucleophosmin (NPM1) in disease pathogenesis through multi-omics approaches.

Methods: We enrolled patients diagnosed with antibody-positive AE and analyzed a broad panel of immunological indicators. Prognostic prediction models were developed using eight machine learning algorithms and validated in an independent cohort. Model interpretability was enhanced through SHapley Additive exPlanations (SHAP) analysis. We further evaluated the therapeutic potential of protein A immunoadsorption (PAIA) in reducing pathogenic antibodies. Building upon these clinical and immunological findings, we sought to investigate the underlying mechanisms by exploring the role of nucleophosmin (NPM1). To this end, we integrated single-cell RNA sequencing and spatial transcriptomics in an experimental autoimmune encephalomyelitis (EAE) model and conducted a phenome-wide association study (PheWAS) to assess its safety as a potential therapeutic target candidate.

Results: Six key immunological indicators were identified for model construction: cerebrospinal fluid /serum IgG quotient (QIgG), lymphocyte count, double negative T cell count, double positive T cell count, NK cell count, and T cell percentage. The RF, XGBoost, and LGBM models demonstrated high predictive performance, with AUC values of 0.978, 0.917, and 0.900, and accuracies of 0.940, 0.916, and 0.831, respectively. Anti-NMDAR antibody titers in cerebrospinal fluid decreased (from 1:3.2 to 1:1) following PAIA treatment in a single patient. Cell communication analysis revealed enhanced intercellular signaling in the high-Npm1 expression group, particularly involving the PSAP pathway. Spatial transcriptomics confirmed upregulated Npm1 expression in EAE lesions. PheWAS indicated no significant off-target effects associated with NPM1.

Conclusion: This study provides an interpretable prognostic framework for AE, presents preliminary evidence for PAIA, and nominates NPM1 as a potential mechanistic player in disease pathogenesis. Its suitability as a potential therapeutic target requires further safety validation, despite the absence of significant signals in the preliminary PheWAS.

Objective: This study investigated how cumulative environmental exposures influence offspring behaviour and inflammation-related molecular signatures in the brain and peripheral immune system.

Methods: A novel "triple-hit" mouse model was developed using C57Bl/6JAusB mice (N = 70), combining preconceptual social stress, antenatal high-fat diet, and a postnatal immune challenge (poly(I:C), 10 mg/kg). At 12 weeks, offspring underwent behavioural tests relevant to neurodevelopmental disorders (NDDs), including the Elevated Plus Maze, 3-Chamber Social Preference, Self-Grooming, and Marble Burying. A composite NDD-risk index was calculated. Single-cell RNA sequencing (scRNA-seq) and bulk proteomics were performed on male triple-hit offspring to identify differentially expressed genes and proteins associated with inflammatory pathways.

Results: Male triple-hit offspring showed elevated NDD-related behavioural risk and social deficits, not observed in females. scRNA-seq revealed altered inflammatory and ribosomal pathways in brain glia and peripheral immune cells. Proteomic analysis showed decreased abundance of proteins involved in inflammation, translation, chromatin remodelling, and synaptic function in both brain and blood.

Conclusion: Combined environmental stressors may drive male-specific behavioural and inflammatory changes relevant to NDDs. The identification of overlapping inflammatory signatures in brain and peripheral immune cells supports a role for shared immune mechanisms in brain-immune axis dysfunction. However, these pathway-level findings should be interpreted as preliminary hypotheses and warrant independent validation to confirm their mechanistic significance.

Background: Interleukin 17 (IL-17) is a primary pathogenic cytokine, and antibodies blocking its function are clinically approved for treating psoriasis. Although Act1 (TRAF3IP2) is an essential multifunctional adaptor in IL-17 signaling, its regulatory mechanisms remain poorly understood. In this study, the role of endoribonuclease N4BP1 in regulating the IL-17 signaling pathway was characterized.

Methods: N4BP1 was knocked out in both in vivo and in vitro experimental models to detect alterations in the IL-17 signaling pathway. Moreover, the specific mechanism by which N4BP1 exerts its regulatory effect was explored by examining the stability, degradation rate, transcription and translation rate of key proteins.

Results: N4BP1 deficiency markedly enhanced IL-17-induced expression of proinflammatory mediators, including CXCL1, CCL20, and MMP9. Unexpectedly, the mRNA stability of CXCL1, CCL20, and MMP9 was largely unaffected by N4BP1 knockout. Further investigation revealed that N4BP1-deficient cells exhibited elevated MAPK phosphorylation, particularly of p38. Pharmacological inhibition of p38 substantially reduced CXCL1, CCL20, and MMP9 levels in N4BP1-deficient cells. This hyperactivation of MAPKs was attributed to an increased protein level of Act1 in N4BP1-deficient cells. Silencing of Act1 with shRNAs in N4BP1-deficient cells greatly diminished the upregulation of CXCL1, CCL20 and MMP9. The elevated Act1 protein level in N4BP1-deficient cells was not due to enhanced Act1 mRNA stability. Instead, polysome profiling demonstrated a pronounced enrichment of Act1 mRNA in the translationally active polysome fraction in N4BP1-deficient cells. In vivo, under pathological stimuli such as IMQ or aging, N4BP1-deficient mice exhibited increased Act1 protein, MAPK phosphorylation, and increased expression of IL-17 downstream genes, including CXCL1, CCL20, and MMP9. Pharmacological inhibition of Act1 ameliorates IMQ-induced skin damage, with a more pronounced therapeutic effect observed in N4BP1 KO mice.

Conclusions: These findings collectively establish that N4BP1 is a potent negative regulator of IL-17 signaling that suppresses the translation of Act1 mRNA.