Inflammation Research最新文献

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.

Background: Pyroptosis, a proinflammatory form of programmed cell death, has emerged as a central driver of chronic inflammation, CD4⁺ T cell depletion, and non-AIDS comorbidities in HIV infection. This review synthesizes current evidence on the molecular mechanisms and pathological consequences of pyroptosis in HIV.

Methods: We conducted a comprehensive analysis of the literature, examining the molecular pathways of pyroptosis triggered by abortive HIV infection, the roles of specific inflammasomes (e.g., AIM2, NLRP3, CARD8) and viral proteins, and the subsequent amplification of inflammation through cytokine release and gut barrier dysfunction.

Results: Abortive infection in resting CD4⁺ T cells generates cytosolic viral DNA, activating inflammasomes (primarily AIM2/IFI16) and executing pyroptosis via GSDMD. This process initiates a vicious cycle of immune activation, mucosal damage, microbial translocation, and systemic inflammation, leading to CD4⁺ T cell loss, reservoir persistence, and end-organ damage. Therapeutic targeting of key nodes (e.g., caspase-1, NLRP3, GSDMD) shows promise in preclinical models.

Conclusion: Pyroptosis is a critical pathological engine in HIV, linking viral infection to chronic immunodeficiency and comorbidities. Adjunctive therapies targeting this pathway may reduce inflammation, preserve immune function, and support strategies toward a functional cure.

Background: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.

Findings: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8⁺T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.

Conclusion: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.

Background: Acute respiratory distress syndrome (ARDS) and systemic immune-mediated damage are two of the severe COVID-19 outcomes that are primarily caused by cytokine storms triggered by dysregulated immune responses. The limited benefits of current immunosuppressive treatments highlight the need for mechanistic understanding to direct focused interventions.

Objective: The dual functions of cytokines in controlling autophagy during SARS-CoV-2 infection are examined in this review, along with the potential for autophagy modulation to limit hyperinflammation and restore immune homeostasis.

Key findings: Emerging evidence suggests that autophagy critically modulates the balance between pro- and anti-inflammatory cytokines in COVID-19. Through anti-inflammatory feedback mechanisms, cytokines contribute to resolution while promoting inflammation in the early stages. The IRE1α-XBP1 axis is activated by SARS-CoV-2-induced endoplasmic reticulum stress, which increases cytokine production and modifies autophagic flux. Concurrently, extracellular vesicles containing cytokines, damage-associated molecular patterns, and viral components are released as secretory autophagy reroutes cytoplasmic cargo toward multivesicular bodies and amphisomes, increasing paracrine immune activation. Suppressed degradative autophagy and increased secretory autophagy-mediated inflammatory signaling are the hallmarks of this pathological state.

Conclusions: In severe COVID-19, targeted autophagy restoration is a promising therapeutic approach to restore immune responses, reduce excessive inflammation, and encourage the resolution of cytokine storms. Restoring immune homeostasis through more targeted immunointerventions may be made possible by modifying autophagy pathways.