Mediators of Inflammation最新文献

Objective: Previous studies suggest a complex interaction between 3,3',5-triiodo-L-thyronine (T3) and inflammation, but this relationship remains unclear. This study investigates the association between free triiodothyronine (FT3) levels and inflammatory markers in the US population using National Health and Nutrition Examination Survey (NHANES) data.

Methods: This study analyzed NHANES data from three cycles between 2007 and 2012, using Spearman correlation tests and multivariate linear regression. Subgroup analyses and interaction tests were conducted based on age, gender, race, body mass index (BMI), thyroid-stimulating hormone, and free thyroxine (T4) to determine the correlations between FT3 and seven systemic inflammatory markers: C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-white blood cell ratio (PWR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI).

Results: A total of 2306 participants were included in this study. Univariate correlation analysis showed that CRP, NLR, MLR, and PLR were significantly negatively correlated with FT3 levels (all p  < 0.05). After adjusting for confounders, FT3 levels were significantly negatively associated with CRP, NLR, and PLR (all p  < 0.05). Subgroup analysis showed that age significantly modified the associations between FT3 and systemic inflammatory markers, such as CRP, NLR, MLR, SII, and SIRI (p-interaction < 0.05). The inverse associations were more consistent among individuals aged ≥ 65 years.

Conclusion: In the general population, FT3 levels exhibit inverse associations with systemic inflammatory markers.

Severe acute pancreatitis (SAP) is associated with high morbidity and mortality. Microcirculatory dysfunction is a critical pathological event in this process and a primary contributor to organ failure (OF). Despite the pivotal role of P-selectin in mediating the adhesion of activated platelets and leukocytes to the vascular endothelium, a process central to microcirculatory dysfunction, effective therapeutic interventions for SAP remain limited. Salvia miltiorrhiza, a traditional Chinese medicinal (TCM) herb, possesses well-documented pharmacological properties, including anti-inflammatory, anticoagulant, and microcirculation-improving effects. This review synthesizes recent advances in understanding the bioactive components of Salvia miltiorrhiza, which ameliorate microcirculation by modulating P-selectin expression and activity through mechanisms targeting its transcription, translation, or post-translational activation. Given the current lack of direct evidence in the context of SAP, we synthesized extensive findings from studies on cardiovascular, gastrointestinal, and inflammatory diseases, as well as from relevant acute pancreatitis (AP)/SAP models. These collective data demonstrate that Salvia miltiorrhiza effectively inhibits platelet aggregation, attenuates leukocyte adhesion, mitigates endothelial injury, and improves perfusion. Substantial evidence suggests that the bioactive compounds derived from Salvia miltiorrhiza function as effective agents against microcirculatory dysfunction by targeting P-selectin. Leveraging this well-defined mechanistic pathway and the promising therapeutic efficacy observed in AP/SAP models, targeting P-selectin with Salvia miltiorrhiza's bioactive compounds emerges as a compelling novel strategy for SAP-associated microcirculatory dysfunction, laying a groundwork for subsequent validation studies.

Background: Intestinal barrier dysfunction is a key driver of ulcerative colitis (UC) recurrence and chronic persistence. Modulating group 3 innate lymphoid cells (ILC3) activity and tryptophan-derived metabolites is crucial for enhancing mucosal repair in UC. Robinia pseudoacacia L. flower exosome-like nanoparticles (RFELNs) could ameliorate intestinal mucosal injury in mice. This study aimed to investigate the impact of RFELNs on intestinal barrier repair in UC mice and explore the underlying mechanisms.

Methods: Changes in body weight, food intake, DAI score, colon length, pathological score, and inflammatory factor level were performed to assess the therapeutic effect of RFELNs on DSS-stimulated UC mouse models. The effects of RFELNs on intestinal barrier integrity were assessed by intestinal barrier permeability analysis, Alcian Blue staining, immunohistochemistry (IHC), and western blot assays. IL-22 level was measured by immunofluorescent staining and ELISA assay. Besides, flow cytometry was performed to detect the proportions of ILC3 and NCR⁺ILC3 in the colon. Subsequently, an in vitro culture system consisting of NCM460 cells and MNK3 cells was established to determine potential mechanism of RFELNs' influence on UC.

Results: RFELNs prominently relieved pathological symptoms in UC mice, including weight loss, enhanced DAI score, shortened colon, and pathological colon damage. Moreover, RFELNs decreased the concentration of FITC-dextran and DAO level and enhanced D-lactate levels. Additionally, RFELNs significantly enhanced the number of colonic goblet cells, restored epithelial tight junctions (TJs), and upregulated TJ protein levels. Moreover, RFELNs enhanced IL-22 expression and the proportion of ILC3 cells and NCR⁺ILC3 cells. The protective effect of RFELNs on UC depends on AhR. Further, RFELNs activated AhR pathway by increasing the content of indole derivatives produced by tryptophan metabolism, thus promoting the repair of intestinal barrier damage.

Conclusion: RFELNs restored intestinal barrier function in UC mice by activating AhR/IL-22 signaling through regulation of gut microbiota-dependent tryptophan metabolism.

Background: Traumatic brain injury (TBI) is an important cause of disability and death worldwide. The development of neuroinflammation after TBI is related to the brain parenchyma. M1-type microglia play important roles in this process, but the specific mechanism through which regulating microglia M1 polarization is still not fully understood. This study aimed to investigate the role of ephrin receptor A4 (EPHA4) in the M1 polarization of microglia after TBI.

Methods: A TBI rat model was established by the controlled cortical impact (CCI) method, and M1 polarization of GMI-R1 cells was induced by lipopolysaccharide (LPS) treatment. Target genes associated with the progression of TBI were screened by transcriptome sequencing; the expression of key genes and proteins was detected by real-time quantitative PCR (RT‒qPCR), Western blot, ELISA, and immunofluorescence, and the damage of the rat brain tissue and the blood-brain barrier (BBB) was evaluated by hematoxylin‒eosin (HE) staining and Evans blue staining.

Results: This study revealed that EPHA4 expression is upregulated in the brain tissue of TBI rats and that treatment with its inhibitor, KYL peptide, can improve the progression of TBI. KYL peptide intervention downregulated the levels of the proinflammatory cytokines and upregulated the levels of the anti-inflammatory cytokines and inhibited the M1 polarization of microglia. The levels of the endoplasmic reticulum stress (ERS)-related proteins and Ca²⁺ were upregulated in TBI rats and downregulated after KYL peptide treatment but subsequently increased after 123C4 treatment. Our results showed that EPHA4 promoted the M1 polarization of microglia by enhancing ERS. Notably, mitogen-activated protein kinase (MAPK) signaling was significantly enriched in TBI. In vitro studies revealed that LPS treatment promoted the activation of MAPK signaling in GMI-R1 cells. A mechanistic study revealed that EPHA4 may activate ERS by activating the MAPK signaling pathway and promote M1 polarization of microglia after TBI.

Conclusion: Our study revealed that the EPHA4/MAPK axis may be a key regulatory factor in controlling microglial M1 polarization during brain injury. Blocking this signaling axis may represent a potential therapeutic approach for improving TBI.

Background: Clinical studies have demonstrated that the systemic immune-inflammation index (SII) is widely used to assess immunity and inflammation in patients. However, the association between SII and atopic dermatitis (AD) remains unclear. This study, based on the National Health and Nutrition Examination Survey (NHANES) database, aims to explore the relationship between SII and AD.

Methods: This study utilized NHANES data from 1999 to 2006, with a total of 8194 subjects included in the final analysis. We examined the associations between AD, SII, and other covariates by analyzing baseline characteristics and performing correlation analyses. Multivariate generalized linear models (GLMs) were used to analyze the correlation between AD and SII risk. A weighted multivariate logistic regression model was applied to examine the association between SII and AD. Additionally, a nomogram was constructed to predict the risk of developing AD. The eXtreme Gradient Boosting (XGBoost) algorithm was employed to evaluate feature importance. Finally, subgroup analysis was performed to further explore the relationship between SII and AD across different subpopulations.

Results: Significant differences were observed between the AD and control groups in terms of race, SII, SII group, and other variables. Furthermore, the p-values for SII (Q2 and Q3 groups) in all three models were less than 0.05, indicating that the influence of SII on the outcome was not significantly affected by other covariates. The weighted multivariate logistic analysis revealed that SII was strongly associated with AD as a risk factor. The nomogram demonstrated good predictive value for AD, and the XGBoost algorithm further confirmed the high predictive value of SII in AD diagnosis. Finally, subgroup analysis highlighted the significance of the association between SII and specific forms of dermatitis in various subpopulations.

Conclusion: Elevated SII is independently associated with increased AD risk. Although the cross-sectional design precludes causal inference, SII represents a cost-effective biomarker for AD risk stratification. Critically, emerging evidence positions SII as a predictor of therapeutic response-particularly to JAK inhibitors and biologics-highlighting its dual utility in risk assessment and precision management of AD.

Microglia-mediated neuroimmune responses have been implicated in central nervous system injury and disease pathogenesis. The α7 nicotinic acetylcholine receptor (α7 nAChR), which is expressed on microglia and participates in microenvironment interactions, is a key mediator of the cholinergic anti-inflammatory pathway. Nicotine activates the α7 nAChR, which may mediate the inflammation of microglia. This study aims to explore the modulatory effects of nicotine on neuroinflammation and its potential indirect neuroprotective effects using an in vitro microglial cell inflammation model. In our study, inflammatory phenotype indicators and molecular mechanisms of HMC3 cells were analyzed. Furthermore, an HMC3 microglia-SH-SY5Y neuronal coculture system was constructed to investigate the indirect neuroprotective effects of nicotine. The results demonstrated that nicotine exerted an inhibitory effect on the lipopolysaccharide-induced HMC3 microglia inflammation, promoted the release of neurotrophic factors, and neuronal survival by altering the immune environment. These effects appear to be mediated through the activation of α7 nAChR, leading to an increase in phosphorylation of PI3K. This study provides important insights into the immunomodulatory functions of low-concentration nicotine in the nervous system and contributes to a deeper understanding of its potential therapeutic applications.

Aims: This study aimed to investigate the effects of low intensity pulsed ultrasound (LIPUS) combined with imipenem (IMI) on inflammatory responses and organ protection in septic rats.

Results: The study involved 230 Sprague-Dawley (SD) rats, with 80 used for survival analysis and 150 for sampling over 72 h. Histological examination (hematoxylin and eosin [H&E] staining) and transmission electron microscopy (TEM) revealed that LIPUS combined with IMI significantly alleviated spleen tissue damage and reduced mitochondrial edema. Key inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 were significantly decreased, while IL-10 levels increased in the LIPUS + IMI group (p < 0.05). The combined treatment also reduced the expression of cytokines, such as IL-1 receptor (IL-1R), nuclear factor kappa B p65 (NF-κB p65), transforming growth factor-beta (TGF-β), and high mobility group protein box 1 (HMGB1), indicating a reduction in inflammation (p < 0.05).

Conclusion and innovation: This study presents a novel approach by integrating LIPUS with IMI, providing a noninvasive and effective strategy to mitigate cytokine storms, optimize antibiotic use, and reduce organ damage in sepsis. The protective effects observed are primarily attributed to the inhibition of the IL-1R/NF-κB signaling pathway, which significantly improves survival outcomes in septic rats. This combined therapy has potential for enhancing sepsis treatment protocols.

Background: Acute lung injury (ALI) is characterized by significant neutrophil infiltration in the lungs, representing a life-threatening condition with diverse etiologies. However, the mechanisms regulating neutrophil-alveolar epithelial interactions and the pathophysiological roles of neutrophil infiltration in ALI remain incompletely understood.

Methods: A dose of 20 mg/kg lipopolysaccharide (LPS) was intratracheally instilled to induce ALI models in 10-week-old male microRNA-223 knockout mice (miR-223^-/-) and wild-type (WT) mice, with control group mice receiving an equal volume of phosphate-buffered saline (PBS). After 24 h of instillation, lung tissues and peripheral blood were collected from the mice. In vivo, quantitative PCR (qPCR) measured miR-223 and neutrophil elastase (NE) mRNA levels, while Western blot (WB), enzyme-linked immunosorbent assay (ELISA), and hematoxylin-eosin (H&E) staining assessed neutrophil extracellular traps (NETs) markers (H3Cit, myeloperoxidase [MPO]), inflammatory cytokines (TNF-α, IL-1β, and IL-6), and lung injury severity. In vitro, HL-60-derived neutrophil-like cells were cocultured with alveolar epithelial cells under LPS stimulation. The roles of the miR-223/NE/NETs axis were further investigated using the NETs inhibitor GSK484 and the NE inhibitor Sivelestat.

Results: WB experiments showed an increase in NETs-related proteins MPO and H3Cit in the lungs of WT ALI mice, with significantly enhanced expression in miR-223^-/- mice. The lung injury scores and mortality rates in miR-223^-/- mice were significantly exacerbated, accompanied by increased neutrophil infiltration in the lungs. Levels of inflammatory factors (TNF-α, IL-1β, and IL-6) in the serum of miR-223^-/- mice were significantly elevated. In vitro coculture experiments demonstrated that miR-223 deficiency in neutrophil-like cells augmented NETs formation and inflammatory responses, leading to increased damage to alveolar epithelial cells. However, in vivo inhibition of NETs with GSK484 or NE with Sivelestat in miR-223^-/- mice significantly attenuated neutrophil infiltration, inflammation, and lung injury, and improved survival. Similarly, Sivelestat pretreatment reduced NET formation and conferred protection against ALI. Consistent with the in vivo findings, inhibition of NETs with GSK484 or NE with Sivelestat in the coculture system similarly attenuated epithelial damage and inflammatory response.

Conclusion: This study reveals that the miR-223/NE axis critically regulates NETs formation, modulating neutrophil inflammatory infiltration and neutrophil-epithelial interactions to exacerbate ALI. These findings provide potential therapeutic targets for ALI.

Autoimmune disorders encompass a varied range of diseases in which the immune system mistakenly targets and attacks the body's own tissues. The causes of the conditions are unknown. It is presumed that various genetic, environmental, and immune factors all play a part. Nowadays, therapies concentrate mainly on anti-inflammatory agents with immunosuppressant medications. New research highlights the central role of decoy receptors (DcRs) in regulating the immune system. DcRs are molecular traps for cytokines and other signaling molecules, preventing them from binding to functional receptors and influencing inflammatory processes. Their activity is context-dependent, shifting the balance between protective and pathogenic responses, and DcR dysregulation has been implicated in the development of autoimmune diseases. Understanding DcR function is critical for the design of potential therapeutic interventions. DcR mechanisms are reviewed here with emphasis on structural and disease-specific functions. Targeting DcRs is a promising strategy to reconstitute immune homeostasis. Understanding the dual regulatory functions and context-dependent mechanisms is critical for designing new therapies that reduce autoimmune pathogenesis without compromising host defense mechanisms.