Journal of Inflammation Research最新文献

Background: CD73, a pivotal enzyme in the purinergic signaling cascade, modulates the concentrations of adenosine and inosine. These metabolites are involved in immune responses and inflammatory processes. This study aims to investigate the function of CD73 in the pathogenesis of inflammatory bowel disease (IBD) and explore the potential mechanism.

Methods: Dextran-Sodium-Sulfate (DSS)-induced colitis mice models were established by orally administering 3% DSS. CD73 was blocked by intraperitoneal injection of Adenosine 5'- (α, β-methylene) diphosphate (APCP). Inosine was supplemented by intraperitoneal injection. Hematoxylin-eosin (H&E), PAS and Alcian blue staining were used to evaluate the inflammation infiltration and colon damage. Serum IL-6 levels were detected by ELISA assay. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to investigate the level of inosine.

Results: Blockade of CD73 by APCP aggravated disease severity in DSS-induced colitis mice models, characterized by increased weight loss, colon shortening and pathological damage, increased disease activity and IL-6 production. Blocking CD73 impairs intestinal barrier function and integrity by reducing the expression of tight junction proteins (claudin-1, occludin and ZO-1), both in colon tissues and intestinal epithelial cell-MODE-K. In addition, APCP increased oxidative stress in colon tissue and MODE-K (increased MDA level, decreased SOD and GSH activities). Moreover, blocking CD73 reduced inosine levels in vivo and in vitro. We found that inosine treatment significantly ameliorated DSS-induced colitis in mice, as demonstrated by decreased weight loss, less colon shortening and histological injury, reduced disease activity and IL-6 production. Notably, the effects of inosine on MODE-K cells were opposite to those of APCP, including the effects on the expression of oxidative stress molecules and tight junction proteins.

Conclusion: This study indicates that CD73 exerts a protective effect in the progress of DSS-induced colitis. Inosine supplementation might be a potential therapeutic strategy for colitis.

Background: The assessment of disease activity in rheumatoid arthritis (RA) is crucial for clinical management. In recent years, composite inflammatory markers, such as the leukocyte-to-albumin ratio (LAR), have demonstrated prognostic value in various diseases; however, its relevance in RA remains unclear. This study aims to investigate the association between LAR and disease activity in RA, as measured by the DAS28-ESR and DAS28-CRP scores.

Methods: This retrospective study enrolled 1070 patients with RA, who were categorized into three groups based on LAR tertiles: T1 (0.06-0.14), T2 (0.14-0.19), and T3 (0.19-0.88). Demographic characteristics, laboratory parameters (including inflammatory markers, complete blood count, and biochemical indicators), and disease activity scores were collected. Univariate analysis, multivariate linear regression, and piecewise linear regression models were employed to evaluate the association between LAR and DAS28 scores, with adjustments for confounding factors such as sex, age, and medication use.

Results: Patients in the high-LAR group (T3) exhibited significantly elevated levels of inflammatory markers (ESR, CRP, and fibrinogen; all P < 0.001) and lower albumin levels (P < 0.001). Univariate analysis revealed a significant positive correlation between LAR and both DAS28-ESR (β = 3.949, P < 0.001) and DAS28-CRP (β = 4.804, P < 0.001). After multivariate adjustment, LAR remained independently associated with DAS28-ESR (β = 1.846, P < 0.001) and DAS28-CRP (β = 2.450, P < 0.001). Piecewise regression analysis identified an inflection point in the LAR-DAS28 relationship at LAR = 0.20. Below this threshold, the association was stronger (DAS28-ESR β = 6.33, P < 0.001), whereas above 0.20, the association was attenuated yet remained significant (β = 2.03, P < 0.001).

Conclusion: LAR is an independent factor associated with disease activity in RA, with a particularly pronounced correlation observed in the lower LAR range. These findings suggest that LAR may serve as a simple and cost-effective auxiliary indicator for clinical assessment of inflammatory status and disease activity in RA.

Background: Chronic exposure to particulate matter (PM) is recognized as a significant contributor to respiratory health complications, including oxidative stress, inflammatory responses, and compromised epithelial barrier function. In this work, we ask whether the transport of potassium and chloride through the large-conductance calcium-activated potassium (BK_Ca) channel and the cystic fibrosis transmembrane conductance regulator (CFTR) channel may change PM-induced epithelial dysfunction.

Methods: This study aimed to evaluate the impact of PM on cell variability, ROS level, inflammation, mitochondrial function, intracellular calcium homeostasis, and epithelial barrier integrity in three different airway epithelial cell lines: wild-type human bronchial epithelial cells (HBE WT), HBE WT cells with disruption of the KCNMA1 gene encoding the α-subunit of the BK_Ca channel (HBE ΔαBK_Ca) with lost potassium transport, and cystic fibrosis bronchial epithelial cells (CFBE) with dysfunction of the chloride transport.

Results: PM exposure significantly increased ROS synthesis and amplified IL-6 and TNF-α release, particularly in HBE ΔαBK_Ca and CFBE cells. Mitochondrial function was also adversely affected, as evidenced by reduced maximal respiratory capacity in both HBE ΔαBK_Ca and CFBE cells relative to HBE WT. In addition, PM-treated HBE ΔαBK_Ca and CFBE cells showed higher intracellular calcium concentrations. Finally, PM exposure resulted in a pronounced reduction in transepithelial electrical resistance (TEER), with CFBE monolayers exhibiting the most significant susceptibility to barrier disruption.

Conclusion: These findings indicate that impaired potassium and chloride transport through the BK_Ca and CFTR channels exacerbates particulate matter-induced oxidative stress, inflammatory responses, mitochondrial dysfunction, and disturbances in calcium homeostasis in airway epithelial cells. Increased susceptibility of HBE ΔαBK_Ca and CFBE cells to PM exposure, underscores the crucial role of proper ion transport in maintaining airway epithelial integrity.

Purpose: While elevated blood eosinophil counts (BECs) are established biomarkers in asthma and chronic obstructive pulmonary disease, their impact on lung function in general populations remains less defined. This multi-ethnicity study examined BEC-lung function associations across diverse populations and employed Mendelian randomization (MR) to explore causal mechanisms.

Patients and methods: Integrated cross-sectional analyses involved three cohorts: Hongtong (n=13,868), NHANES (n=11,833), UK Biobank (UKB; n=428,610). Longitudinal assessment used UKB data (n=38,532). Multivariable regression assessed BEC associations with FEV₁, FVC, FEV₁/FVC, and PEF. Linear mixed-effects models estimated longitudinal changes by baseline BEC. Two-sample MR used European/Asian genetic instruments. Subgroup analyses assessed age, sex, disease status, and smoking effects.

Results: BECs consistently showed inverse associations with FEV₁ across cohorts, strongest in UKB (266.22 mL and 171.95 mL FEV₁ reduction per 1×10⁹ cells/L BEC increase in males and females, respectively). Associations with FVC, FEV₁/FVC, and PEF were most pronounced in UKB, whereas significant associations were absent for FVC in Hongtong and NHANES males. Longitudinally, higher baseline BECs predicted accelerated lung function decline, especially in males. Subgroup analyses revealed intensified negative associations in smokers and individuals >45 years. Importantly, these inverse associations persisted in sensitivity analyses excluding individuals with respiratory diseases. MR showed significant association in all traits in Europeans (P<0.05) but only for FEV₁/FVC in Asians.

Conclusion: BECs show a significant and independent association with lung function impairment at the population level. MR analyses provide supportive evidence for a potential causal role, identifying distinct patterns of airway obstruction in Asian populations versus broader lung function deficits in Europeans. Variations by sex, ancestry, age, and smoking underscore demographic considerations in eosinophil-related respiratory health. These findings suggest the potential utility of monitoring BECs in asymptomatic individuals and warrant further investigation into personalized prevention strategies.

Introduction: The rising incidence of inflammatory skin diseases, including psoriasis, has necessitated new treatment approaches. This paper focuses on the development of a hibiscetin-impregnated nanogel that reduces the severity of skin inflammation.

Methods: Imiquimod (IMQ) was used to induce psoriasis-like inflammation in animal models, and the nanogel's worthiness was compared. Nanogel was prepared in different concentrations of hibiscetin, namely F1 (1) and F2 (2), and characterized in terms of appearance, size, charge, spreadability, pH, release kinetics of the drug, skin penetration and stability.

Results: Lab analyses showed that the nanogel possessed desirable characteristics, with an average particle size of 205 nm, a polydispersity index (PDI) of 0.385, and a surface charge of -69.5 mV. Its morphology was confirmed to be spherical by scanning electron microscopy (SEM). The nanogel demonstrated powerful anti-inflammatory properties, including the disappearance of redness and skin thickening, reduced pro-inflammatory cytokine concentrations, reduced oxidative stress markers, and apoptosis-mediated cell death in vivo. Hibiscetin, as an effect of IMQ, also had a reparative effect on damaged skin as evidenced by histopathological studies.

Conclusion: The results imply that hibiscetin-conjugated nanogels offer an option for improving the delivery and therapeutic efficacy of inherent compounds in the management of skin inflammation.

This review methodically elucidates the pivotal role of neutrophils in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). A body of research indicates that neutrophils are preactivated in a background of systemic metabolic dysregulation. Furthermore, neutrophils are specifically recruited to the liver via the CXCR2/CXCL1 axis. In the liver microenvironment, neutrophils directly mediate hepatocyte injury and potently amplify inflammation through synergistic mechanisms. These mechanisms include degranulation, the release of toxic proteases, the production of reactive oxygen species, and the formation of neutrophil extracellular traps. More crucially, neutrophils have been shown to promote disease progression from simple fatty liver to non-alcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma by forming complex interaction networks with macrophages, hepatic stellate cells, and hepatocytes. These findings not only deepen our understanding of the immunopathological mechanisms of NAFLD but also highlight the immense clinical translational potential of neutrophils as novel biomarkers and therapeutic targets.

Sepsis is a life-threatening syndrome characterized by infection-induced systemic inflammation and immune dysregulation, commonly resulting in the development of multiple organ dysfunction syndrome (MODS), a leading cause of mortality in clinical practice. In decades, immunometabolic reprogramming has been identified as a critical mechanism that contributes to the progression of sepsis and the associated organ injuries. The review provides a systematic overview of the metabolic alterations in immune cells and organs in experimental models of sepsis. Key features include enhanced glycolysis, impaired mitochondrial function, and disturbed lipid metabolism, all of which are closely associated with organ damage. These metabolic adaptations influence immune responses and cell fate decisions, inter-organ crosstalk, and the development of MODS. A detailed examination is conducted on the temporal progression of pathological changes in established animal models, along with organ-specific metabolic dysfunctions and novel therapeutic targets. It emphasizes the importance of dynamic immunometabolic regulation, tissue-specific responses, and inter-organ interactions in the context of sepsis treatment. The integration of multi-omics technologies, identification of reliable biomarkers, and the development of personalized therapeutic strategies should be used to facilitate clinical translation of mechanistic insights.

Background: Acute respiratory distress syndrome (ARDS) induced by sepsis is a clinical syndrome characterized by high morbidity and mortality rates. This study aims to clarify the effects of recombinant mouse IL-27 protein on macrophage ferritinophagy, macrophage polarization, and its interventional role in sepsis-induced ARDS.

Methods: This study utilized wild-type (WT) and IL-27 receptor knockout (IL-27R^-/-) mice to establish a cecal ligation and puncture (CLP)-induced sepsis model. The post-modeling mice were randomly divided into four groups: control group, CLP model group, IL-27 combined with CLP treatment group, and IL-27+CLP+PROTAC NCOA4 degrader-1 (Compound V3, CV3) combined treatment group. For the in vitro experiments using RAW 264.7 cells and Bone Marrow-Derived Macrophages (BMDMs), the cells were divided into four main groups as follows: the control group, the lipopolysaccharide (LPS) model group, the LPS+IL-27 treatment group, and the LPS+IL-27+CV3 combination treatment group.

Results: This study investigates the role of IL-27 in exacerbating ferritinophagy and ferroptosis in macrophages and septic lung injury, and explores the therapeutic potential of the NCOA4 degrader CV3. We found that IL-27 synergizes with LPS to enhance NCOA4-mediated ferritinophagy, leading to increased degradation of FTH1, upregulation of LC3A/B, and promotion of ferroptosis. Ferritinophagy amplification drove M1 macrophage polarization and inflammatory cytokine release. CV3, a PROTAC-based NCOA4 degrader, effectively disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy, and mitigated ferroptosis and inflammation. In murine models of sepsis-induced ARDS, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis. Notably, IL-27R^-/- mice were resistant to IL-27-induced exacerbation of ferritinophagy and lung injury, confirming the specificity of IL-27 signaling.

Conclusion: These findings reveal a potential mechanistic link between NCOA4-mediated ferritinophagy and sepsis-associated ARDS pathogenesis. Targeting this pathway with CV3 may offer a novel therapeutic strategy, which warrants further investigation.

Sepsis-induced endothelial dysfunction and the resultant capillary leak syndrome are defining features of septic shock, posing a profound challenge to conventional fluid resuscitation strategies. The long-standing debate over crystalloid versus colloid administration is evolving beyond a simple dichotomy toward a more nuanced, physiologically informed approach. This review critically examines the pathophysiological cascade driving vascular hyperpermeability in sepsis-from endothelial glycocalyx degradation and inflammatory cytokine storms to oxidative stress and nitric oxide dysregulation. We trace the evolution of resuscitation paradigms from early goal-directed therapy to modern conservative approaches, highlighting the limitations of crystalloid-dominant protocols, including intravascular volume depletion despite a positive fluid balance and iatrogenic organ injury. Drawing on evidence from landmark clinical trials (eg, ALBIOS, CRISTAL, SMART) and a pharmacological reappraisal of fluid properties, we argue that a one-size-fits-all strategy is obsolete. Instead, this narrative review synthesizes recent trial evidence and pathophysiological insights to propose the Phase-Adapted, Endothelium-Sparing (PAES) resuscitation strategy, a novel framework that tailors fluid type and volume to the distinct temporal phases of septic shock: Rescue, Optimization, Stabilization, and De-escalation. This model advocates for initial resuscitation with balanced crystalloids, followed by the judicious integration of albumin in specific, high-risk patient subgroups to leverage its unique oncotic and pleiotropic, endothelium-stabilizing effects. We further outline how dynamic hemodynamic monitoring, point-of-care ultrasound, and emerging biomarkers of endothelial injury (eg, syndecan-1, angiopoietin-2) can guide the real-time implementation of this personalized strategy. The PAES framework aims to uncouple macrohemodynamic stabilization from microcirculatory injury, offering a pragmatic pathway to optimize perfusion, mitigate capillary leak, and improve outcomes in this critically ill population.

Objective: This study aimed to elucidate the molecular mechanisms of berberine (BBR) in ameliorating diabetic kidney disease (DKD), focusing on its regulatory effects on the renal immune microenvironment and macrophage polarization.

Methods: We first employed a network pharmacology approach, integrating public transcriptomic data with drug target databases, to predict the core pathways and immune regulatory mechanisms of BBR in DKD. To experimentally validate these in silico predictions, we assessed the effects of BBR on apoptosis, fibrosis, and inflammation in a high-glucose-induced renal tubular epithelial cell (NRK-52E) model. Finally, a DKD rat model was established to confirm the therapeutic efficacy in vivo and to mechanistically investigate BBR's impact on renal macrophage polarization and the key signaling proteins of the predicted pathway.

Results: Network pharmacology and transcriptomic analysis identified 55 core genes of BBR in DKD, enriched in apoptosis, metabolism, oxidative stress, and inflammation, with immune infiltration implicating T cells, B cells, and macrophage subsets. In vitro, BBR enhanced viability of high-glucose-injured NRK-52E cells, suppressed apoptosis and fibrosis markers, and reduced IL-6, IL-17A, and TNF-α levels. In vivo, BBR reduced hyperglycemia, preserved renal function, attenuated fibrosis, and rebalanced macrophage polarization by inhibiting M1 while promoting M2 phenotypes. Mechanistically, these effects were associated with downregulation of the IL17A/TRAF6/MAPK14 pathway.

Conclusion: Berberine alleviates diabetic kidney disease by regulating macrophage polarization via inhibition of the IL17A/TRAF6/MAPK14 signaling pathway, underscoring its therapeutic potential as an anti-inflammatory and anti-fibrotic agent.