Inflammation Research最新文献

Mitochondrial dysfunction drives Rheumatoid Arthritis (RA) progression by disturbing energy metabolism and promoting inflammation. Additionally, the female predominance of RA highlights estrogen deficiency as an important contributor to disease development. The effect of estrogen in RA has been investigated; however, its specific effects on the mitochondrial proteome and function have yet to be studied. This study investigated the effects of 17-β estradiol (E2) on the mitochondrial proteome of patient-derived RA fibroblast-like synoviocytes (RA-FLS) using Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS) analysis, followed by an assessment of key mitochondrial functional parameters and in vitro validation. The results identified an upregulated expression of two mitochondrial proteins, Acyl-CoA dehydrogenase very long chain (ACADVL) and ATP synthase subunit O (ATP5O), after E2 treatment in RA-FLS. This was further validated by increased real-time ATP production and reduced glycolytic capacity, along with increased expression of proteins related to fatty acid β-oxidation. In addition, E2 influenced mitochondrial dynamics by modulating the fission-fusion balance, resulting in improved mitochondrial morphology. E2 treatment also reduced the expression of mitophagy markers and increased mitochondrial membrane potential, indicating improved mitochondrial function. It also lowered mitochondria-centered oxidative stress by upregulating mitochondrial antioxidant enzymes. Mitochondrial proteomics analysis thus, demonstrated that E2 has the potential to enhance mitochondrial energy metabolism and alleviate mitochondrial dysfunction in RA. These findings provide a foundation for further exploration of mitochondria-targeted therapeutic approaches in RA management.

Objective: To investigate the expression of ferroptosis-related molecules in macrophages of community-acquired pneumonia (CAP) patients and explore their association with disease severity. This study provides novel insights into the role of ferroptosis in CAP pathogenesis by integrating transcriptome sequencing, RT-qPCR, Western blot, and flow cytometry analyses.

Methods: Ferroptosis-related molecules were analyzed in CD14⁺ monocytes and CD11b⁺ macrophages from CAP patients using transcriptome sequencing, RT-qPCR, Western blot, and flow cytometry. Clinical data from CAP patients (n = 46) and healthy controls (n = 63) were compared.

Results: CAP patients exhibited elevated levels of ferroptosis markers (PTGS2, Fe²⁺, and lipid peroxides) and downregulation of inhibitors (TP53 and GPX4). Transcriptome analysis showed activation of the ferroptosis pathway, with significant changes correlating with disease severity. Elevated neutrophil counts and decreased lymphocyte levels were also observed in CAP patients.

Conclusion: Ferroptosis is intricately involved in CAP pathogenesis, with altered expression of key molecules contributing to disease progression. Our findings highlight the potential of targeting ferroptosis-related molecules (e.g., TP53, GPX4, and PTGS2) as a novel therapeutic strategy to mitigate inflammation and tissue damage in CAP. Future studies should validate these findings in larger cohorts.

Emerging evidence indicates that upper and lower airway diseases share anatomical and pathophysiological features. Infections often begin in the upper airway and progress downward, suggesting common immunological mechanisms. Mucin 1 (MUC1), a membrane-bound glycoprotein abundantly expressed in airway epithelial cells, has attracted increasing attention for its immunoregulatory and barrier functions. This review summarizes recent findings on MUC1's involvement in airway inflammation driven by Th1, Th2, and Th17 immune responses. In Th1-type inflammation, MUC1 negatively regulates Toll-like receptor (TLR)-NF-κB signaling pathways, thereby limiting excessive inflammatory responses to bacterial and viral infections. In Th2-type inflammation, MUC1 influences eosinophil survival, maintains epithelial integrity, and modulates glucocorticoid sensitivity, exerting both protective and pathological effects. In Th17-type inflammation, characterized by neutrophil infiltration and elevated IL-17A and IL-22, MUC1 expression alleviates chronic inflammation and may impact microbiome dysbiosis. While MUC1's roles in lower airway disorders are increasingly understood, its specific function and regulatory mechanisms in upper airway diseases remain unclear. This review adopts the unified airway disease (UAD) framework to examine the endotype-specific roles of MUC1 across the upper and lower airways. Rather than providing a disease-by-disease summary, we synthesize evidence through Th1/Th2/Th17 endotypes, link shared mechanisms to biomarker-based patient stratification, and outline MUC1-targeted therapeutic strategies. By applying an endotype- and UAD-centered perspective, the review distinguishes itself from previous work and highlights actionable opportunities for precision medicine. Furthermore, we emphasize the translational potential of MUC1 as both a diagnostic biomarker and a therapeutic target, focusing on advances in small peptides, monoclonal antibodies, RNA interference, and natural compounds that modulate MUC1-related pathways. These developments may ultimately enable the creation of personalized therapies for airway inflammation.

Background and objective: Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis (UC), are chronic conditions characterized by intestinal inflammation. Soluble fiber is fermented by gut microbiota into short-chain fatty acids (SCFA), which possess anti-inflammatory properties. This review aimed to assess the efficacy of oral and topical SCFA administration in patients with UC.

Methods: A systematic review with meta-analysis was conducted in accordance with PRISMA guidelines. Meta-analyses were performed using means and standard deviations to assess clinical and histological outcomes. Endoscopic criteria were also evaluated to determine the effectiveness of the intervention.

Results: Nine studies compared SCFA supplementation with standard therapy, and one employed a crossover design. Oral SCFA, when combined with standard treatment, as associated with reductions in fecal calprotectin and C-reactive protein levels. Meta-analyses of topical SCFA administration revealed a standardized mean difference of - 0.29 ± 0.22, (95% CI: - 0.65 to 0.07; heterogeneity I² = 28%) for the Ulcerative Colitis Disease Activity Index score, and - 0.73 ± 0.61, (95% CI: - 1.58, 0.12; heterogeneity I² = 64%) for histological scores. Endoscopic scores decreased in both intervention and control groups. No adverse effects were observed.

Conclusion: SCFA administration, either orally or topically, has been investigated as a potential adjunct to standard UC therapies. However, the current evidence is limited, particularly for oral administration, which has only been assessed in two studies. Further research is needed to clarify the potential role of SCFA administration.

Interleukin-15 (IL-15) is a pleiotropic cytokine of the common γ-chain (γc) family, playing a central role in the development, survival, and activation of natural killer (NK) cells and memory CD8⁺ T cells. Its tightly regulated expression is essential for maintaining immune homeostasis, while dysregulation of IL-15 signaling has been implicated in the pathogenesis of various autoimmune and chronic inflammatory diseases. This review explores the structural features, receptor complex, and signaling mechanisms of IL-15, emphasizing its immunomodulatory functions in both innate and adaptive immunity. We highlight the role of IL-15 in the initiation and progression of autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), type 1 diabetes, celiac disease, inflammatory bowel disease, psoriasis, and ankylosing spondylitis. Special focus is given to IL-15-mediated activation of tissue-resident memory T cells (TRM), cytotoxic CD8⁺ T cells, and NK cells, which contribute to tissue-specific autoimmunity and sustained inflammation. Furthermore, we summarize emerging therapeutic strategies targeting IL-15 and its receptor complex, including monoclonal antibodies, receptor antagonists, and cytokine fusion proteins. Clinical trials and preclinical data suggest that IL-15 blockade may offer a promising therapeutic avenue in autoimmune diseases, particularly in refractory or relapsing forms. The review concludes with future directions for integrating IL-15-targeted interventions into precision immunotherapy.

Objective: This multiomics study investigated causal relationships between the gut microbiota (GM), immune dysregulation, and amyotrophic lateral sclerosis (ALS) pathogenesis using Mendelian randomization (MR) with experimental validation.

Materials: Analyses incorporated genome-wide data from 87,347 participants (GM: n = 7738; ALS: 20,806 patients, 59,804 controls; immune phenotypes: n = 3757), transcriptomic data from 71 subjects (56 ALS patients, 15 controls), and experimental validation in matched cohorts (n = 6 subjects per group).

Methods: Two-sample bidirectional MR and mediation analysis were used to evaluate associations. Experimental validation employed flow cytometry for myeloid-derived suppressor cell quantification, enzyme-linked immunosorbent assay for cytokines, and real-time polymerase chain reaction for bacterial validation. Statistical analyses included inverse variance weighted methods with Cohen's d calculations.

Results: Sixteen bacterial taxa, including p_Firmicutes.c_Clostridia, displayed protective associations with the risk of ALS, whereas sixteen showed harmful associations. Mediation analysis suggested that p_Firmicutes.c_Clostridia may confer protection through CD33+HLA-DR-myeloid-derived suppressor cell upregulation (23.8% mediation effect). Experimental validation confirmed fewer myeloid-derived suppressor cells in ALS patients (4.0 ± 0.8% vs. 7.5 ± 1.0%, p < 0.001, Cohen's d = 1.4) and lower levels of anti-inflammatory cytokines (TGF-β1: Cohen's d = 1.8, p < 0.001).

Conclusions: These findings support causal associations between gut microbial taxa and the ALS risk, which are mediated through immunoregulatory mechanisms, highlighting therapeutic targets within the gut‒immune‒brain axis.

Background: Neuroinflammation plays a recognized role in the pathogenesis of Spinocerebellar Ataxia Type 3 (SCA3). However, the involvement of systemic inflammatory responses in SCA3 remains poorly defined.

Objectives: Our study aimed to characterize peripheral inflammation in patients with SCA3, examine the relationship between peripheral inflammatory biomarkers and clinical/genetic features, and evaluate the diagnostic utility of these markers.

Methods: The cross-sectional study enrolled 101 patients with SCA3 and 101 healthy controls (HCs). The differences in peripheral inflammatory markers between patients with SCA3 and HCs were assessed. Multivariate linear regressions were used to analyze the associations between blood cell count-derived indices, C-reactive protein (CRP), and clinical/genetic features of SCA3. ROC curves were conducted to assess the potential of these markers to distinguish patients with SCA3 from HCs.

Results: Compared to HCs, patients with SCA3 exhibited significantly higher levels of leukocytes, neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammatory index (SII), systemic inflammatory composite index (AISI), and CRP (adj. p < 0.05). Age influenced lgCRP, NLR, MLR, and lg(neutrophil-to-platelet ratio) (p < 0.05). CAG affected MLR and AISI (p < 0.05). The combination of BMI, monocytes, NLR, and SII differentiated patients with SCA3 from HCs (AUC = 0.779).

Conclusion: Patients with SCA3 display distinct peripheral inflammatory profiles, which correlate with clinical/genetic factors. These peripheral inflammatory markers hold promise as potential tools for diagnosing and monitoring SCA3.

Background: Apolipoprotein E (ApoE) promoted neutrophilic airway inflammation in mice with allergic asthma. Although group 2 innate lymphoid cells (ILC2s) have been established as pivotal mediators in allergic rhinitis (AR) pathogenesis, endogenous mechanisms regulating their hyperactivity are undefined. Whether ApoE has effects in ILC2s in AR is still unknown.

Objective: The aim of this investigation is to identify the crucial function of the suppressor modulator ApoE in regulating ILC2-mediated allergic airway inflammation.

Methods: A cohort comprising 15 pediatric AR patients and matched healthy controls was enrolled to assess serum ApoE messenger RNA (mRNA) expression and protein levels and their relationship with interleukin (IL)-5, IL-13 and total nasal symptoms scores (TNSS). In vitro experiments employing flow cytometry and enzyme-linked immunosorbent assay (ELISA) validated the regulatory effects of ApoE on ILC2s expansion capacity and cytokine secretion. Transcript levels of GATA binding protein 3 (GATA3) and retinoid acid receptor related orphan receptor alpha (RORα) was examined using quantitative reverse transcription polymerase chain reaction (qRT-RCR). The changes of IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) levels after stimulation of human nasal epithelial cells (HNECs) by Dermatophagoides pteronyssinus (Der p), ApoE and anti-Low-Density Lipoprotein Receptor (LDLR) were determined by ELISA. The effects of ApoE and anti-LDLR in vivo were using the ovalbumin (OVA)-induced murine model.

Results: Clinical analyses indicated elevated serum ApoE mRNA and protein levels in AR patients, positively correlating with TNSS. Recombinant ApoE effectively promoted ILC2 activation in PBMCs from AR patients, inducing GATA3 and RORα expression and IL-5, IL-13 secretion, while these effects of ApoE were eliminated by anti-LDLR. Mechanistically, ApoE augmented the epithelial-ILC2 crosstalk by inducing nasal epithelial TSLP/IL-25/IL-33 release. Additionally, our studies have revealed that the anti-LDLR effectively reversed the effects of ApoE on those cytokine production. In vivo, administering anti-LDLR to AR mice effectively alleviates OVA and ApoE induced allergic airway inflammation, reducing eosinophilic infiltration and nasal symptoms, as well as OVA specific immunoglobulin E (IgE) and ILC2 proliferation.

Conclusions: As our findings demonstrate, targeting the ApoE-LDLR axis has considerable therapeutic promise in treating ILC2-dependent allergic airway inflammation.

Background: Lung disease remains a leading cause of global morbidity and mortality, with prevalence strongly influenced by lifestyle factors, including dietary patterns such as the Western diet. Chronic lung inflammation, driven by dysregulated immune responses, is a hallmark of many pulmonary conditions and exacerbates disease progression and severity Emerging evidence highlights potentially critical role of for Dietary fibre and it's metabolites particularly short chain fatty acids (SCFAs), acetate, butyrate and propionate, in modulating the gut-lung axis and regulating pulmonary immune response.

Objective: This review summarizes current evidence on how dietary fibre and SCFAs influence pulmonary immunity and inflammation through systemic and local mechanisms.MethodsLiterature on dietary fibre intake, SCFA production, and immune regulation in the context of lung disease was reviewed to identify key effects and mechanistic insights.

Findings: SCFAs, including acetate, butyrate, and propionate, are produced by gut microbial fermentation of fibre and act via G-protein coupled receptor signalling and histone deacetylase inhibition. These metabolites modulate epithelial and immune cell function, reduce inflammation, and enhance lung immune protection. Beyond local effects, SCFAs influence hematopoietic cells in the bone marrow, altering their recruitment and activity in the lung.

Conclusions: Dietary fibre intake and SCFA-mediated gut-lung immune regulation represent a promising area for therapeutic development. A deeper understanding of these pathways may support novel strategies for the prevention and treatment of respiratory diseases.