Inflammation Research最新文献

Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.

Objective: This study aimed to identify the potential inflammatory molecular biomarkers that could be utilized for the early prediction of different subtypes of tuberculosis (TB) in adults.

Methods: Plasma samples were obtained from a cohort of adults diagnosed with 48 cases of active TB, including drug-susceptible TB (S-TB, n = 28), multidrug-resistant TB (R-TB, n = 20), latent TB infection (LTBI, n = 20), as well as a control group of healthy individuals without any infection (HC, n = 20). The expression level of 92 inflammatory-related proteins was detected by using the high-throughput Olink proteomics platform.

Results: There were 47 inflammatory proteins showing a significant difference (p < 0.05) among TB, LTBI, and HC groups, and 7 of them differed significantly between HC and LTBI groups, 43 proteins differed considerably between LTBI and TB groups, and overall, CXCL10 and TGF-alpha proteins differed substantially among the three groups which could be used as potential diagnostic biomarkers. Furthermore, SCF demonstrates remarkable discriminatory power in distinguishing TB from LTBI, with an area under the curve (AUC) score of 0.920. SLAMF1 has emerged as the top predictor for distinguishing Sputum Culture-Negative from positive tuberculosis cases, with an AUC of 0.779. The Correlation analyses showed various relationships among co-differentiated proteins. In LTBI versus HC, TGF-alpha and CXCL10 had a strong positive correlation. In non-severe versus severe TB, CXCL10 and CXCL9, as well as TNF and CCL3, were strongly positively correlated, while IL-6 and SCF had a negative correlation. These co-differentiated proteins were found to be enriched in various biological processes and molecular functions related to immune regulation and signaling pathways, such as the p53 signaling pathway, the TNF signaling pathway, and the NF-kappa B signaling pathway, highlighting the complex interplay of these proteins in the immune response to TB infection.

Conclusion: Inflammation-related proteins exhibited distinct expression profiles in various conditions of TB. These proteins are intercorrelated and involve the pathogenesis of tuberculosis by activating diverse immune cells and promoting the secretion of pro-inflammatory cytokines. Their functions influence cellular phenotypes, which play a crucial regulatory role in the interaction between the host and Mycobacterium tuberculosis. These findings suggest that these proteins are potential disease prevention and treatment targets.

In this study, systemic and localized immunity induced by SARS-CoV-2 variants of concern or interest (VOC/VOI) was investigated. For that, serum and tracheal aspirate soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were measured in severe COVID-19 patients under mechanical ventilation upon infection with different SARS-CoV-2 variants, namely Alpha, Gamma, Zeta, Delta and Omicron. Increased levels of soluble mediators were observed in serum from severe COVID-19 patients regardless of the variant. In tracheal aspirate samples, the patients infected with the Gamma, Zeta, Delta, and Omicron variants exhibited reduced levels of inflammatory cytokines when compared to those infected with the Alpha variant. The trend of lower cytokine levels was also observed in the serum of patients across these variants, except for the Delta variant. By using network analysis and cytokine storm signatures, the data confirmed that severe COVID-19 induced by different variants have a completely divergent pattern of connectivity in serum samples as well as tracheal aspirates. Patients infected with variants at later time points in the pandemic such as Omicron exhibited networks of weak central architecture in serum samples as compared to tracheal aspirates, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. By and large, this study points out to important systemic and local divergences and to loss of airway localized immunity in severe COVID-19 patients infected with SARS-CoV-2 variants, which brings insight into understanding host responses and viral escape vis-à-vis the virus mutations and evolution.

Aim: Inflammatory pain arises from tissue stress or injury and is initiated by signaling molecules that stimulate the immune and nervous systems. Evidence suggests that purinergic signaling pathways can modulate pain and inflammation through the activation of P1 and P2 purinergic receptors, such as the P2X3 receptor, which are stimulated by extracellular molecules like adenosine triphosphate (ATP). Electroacupuncture (EA) exhibits precise mechanisms that modulate inflammatory pain through the activation of the P2X3 receptor.

Objective: This review analyzed evidence regarding the role of electroacupuncture and the purinergic system, particularly the P2X3 receptor, in modulating inflammation and pain.

Materials and methods: A search for the most relevant articles available in the SciVerse Scopus and MEDLINE/PubMed databases was conducted for publications from 1995 to 2024. Articles were initially selected by reading the title, abstract, and main text, respectively.

Results: It was found that the P2X3 receptor, as well as the molecules activating purinergic receptors, such as ATP and adenosine, have the potential to regulate pain and inflammation. Additionally, EA can modulate the purinergic system in an anti-inflammatory response. EA may stimulate analgesia mainly through the conversion of ATP to adenosine, a crucial molecule in pain control.

Conclusion: The purinergic system directly influences inflammatory pain and controls inflammation. In this context, EA has the potential to orchestrate this system to control pain and inflammation.

Background: Luteolin has an anti-inflammatory effect, but the mechanism has not been elucidated in sepsis-induced acute hepatic injury (AHI). The purpose of this study was to investigate the effects and potential mechanisms of luteolin on sepsis-induced AHI.

Methods: In this study, we utilized both wild-type (WT) mice and Toll-like receptor 4 (TLR4)-deficient (TLR4^-/-) mice alongside RAW264.7 cells. We constructed a CLP-induced AHI mouse model to study the effects of luteolin on liver inflammation, survival and liver macrophage subtypes in mice. In addition, we extracted mouse serum, mouse bone marrow-derived macrophages (BMDMs) and liver tissue and analysed the effects of luteolin on macrophage polarization subtypes and downstream inflammatory cytokines by flow cytometry, ELISA, Western blotting (WB) and qPCR. To further verify the effect of luteolin on macrophage polarization and explore the possible potential mechanism, we used a CLP-induced AHI mouse model and LPS-stimulated RAW 264.7 macrophages to assess the effect of luteolin on macrophage polarization; the expression of TNF-α and IL-10 in the cell culture supernatant; and the expression of iNOS, ARG-1, NF-κB (P65), p-P65 and MyD88 by flow cytometry, ELISA, immunohistochemistry and Western blotting.

Results: We found that luteolin reduced liver injury and inflammatory response and improved the survival rate of mice. Luteolin modulated the macrophage subtype proportion, promoted the change of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and reduced the inflammatory response both in vivo and in vitro. Moreover, luteolin reduced the expression of NF-κB (p-P65), TLR4 and MyD88. By integrating the predictions from network pharmacology with the in vitro and in vivo experimental results, it was determined that the mechanism by which luteolin alleviates sepsis-induced acute hepatic injury is closely related to the TLR4/MyD88/NF-κB pathway.

Conclusions: The results of this study suggest that luteolin helps alleviate liver injury, reduces the expression of proinflammatory cytokines and promotes the expression of anti-inflammatory factors in sepsis-induced acute hepatic injury. This effect may be related to the regulation of macrophage polarization by luteolin through the TLR4/MyD88/NF-κB signalling pathway.

Objective: This study aimed to explore the effect of Roquin-1 on rheumatoid arthritis (RA) and its potential mechanisms.

Methods: Firstly, we used TNF-α to stimulate fibroblast-like synoviocytes (FLSs) to establish an in vitro model of RA. Moreover, a rat model of RA was established with bovine type II collagen and complete Freund's adjuvant. EdU and transwell assays were applied for evaluating the proliferation and migration of FLSs. The multiple mRNA and proteins expressions in FLSs and rats synovial tissues were measured using qRT-PCR, ELISA, western blot, immunohistochemistry staining and immunofluorescence staining. Double immunofluorescence staining and co-IP assay were used to validate the protein interaction between Roquin-1 and Regnase-1. Additionally, cycloheximide (CHX) chase assay was applied for assessing the degradation of fibroblast growth factor 2 (FGF2). Besides, the state of synovial hyperplasia and articular cartilage were also evaluated using HE and Safranin O/Fast Green staining.

Results: The mRNA and protein expressions of Roquin-1 were significantly reduced in TNF-α-stimulated FLSs and the synovial tissues of RA rats. Roquin-1 interacted with Regnase-1 to promote FGF2 degradation and further inhibit the proliferation, migration and inflammation response in TNF-α-stimulated FLSs. Moreover, we also demonstrated that Roquin-1 interacted with Regnase-1 to inhibit NF-κB pathway via suppressing FGF2 expression in TNF-α-stimulated FLSs. In addition, Roquin-1 suppressed inflammatory response in RA rats.

Conclusion: Our findings demonstrated that Roquin-1 could interact with Regnase-1 to inhibit the progression of RA via suppressing FGF2 expression and NF-κB pathway.

Objective and design: Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs.

Material or subjects: We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms.

Results: Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury.

Conclusions: We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.

Background and objective: Asthma is a chronic inflammatory disease characterized by dysregulated cytokine expression. The RNA-binding protein KSRP reduces the expression of several pro-inflammatory mediators. Therefore, we investigated whether KSRP modulates Th2-associated immune responses in vivo in an ovalbumin-induced (OVA) allergic asthma model in C57BL/6 KSRP-deficient mice (KSRP^-/-).

Methods: Asthma severity in OVA-immunized wild type or KSRP^-/- mice was determined by airway hyperresponsiveness (AHR), structural changes of lung tissue, and OVA-specific antibody production. Cytokine expression in bronchoalveolar lavage fluid (BALF) was measured by Cytometric Bead Array (CBA) analysis. Cellular signaling pathways involved in KSRP-mediated effects in asthma pathogenesis were analyzed in vitro in cell culture models using specific inhibitors.

Results: KSRP deficiency exacerbates OVA-induced allergic asthma compared to wild type mice, as indicated by increased AHR, more severe lung damage, goblet cell hyperplasia and increased OVA-specific antibody production. CBA analyses confirmed, that KSRP deficiency enhances IL-4, IL-5 and IL-13 production in BALF. The effect of KSRP on Th2-associated cytokine expression appears to be mediated by modulation of the STAT6 and NFAT signaling pathway rather than by inhibiting the stability of cytokine-encoding mRNA species.

Conclusion: Our data demonstrate that KSRP dampens Th2 immune cell activity and therefore seems to be important for the pathogenesis of Th2-mediated diseases.

Objective: Severe steroid hyporesponsive asthma is a heterogeneous group of chronic inflammatory diseases characterized by irreversible airflow limitation, hyperresponsiveness, inflammation, and remodelling of the airways. Severe asthmatics account for more than 60% of asthma-related healthcare cost worldwide given they are hyporesponsive to corticosteroids and due to the absence of targeted treatment specifically for the T helper-17 (Th-17) high endotype. Hence, there is a clear unmet need to investigate other treatment options to control patients' symptoms. The role of the NLRP3 inflammasome pathway has been highlighted in the literature to contribute to disease pathogenesis and severity. Interestingly, vitamin D3 is an important regulator of the NLRP3 inflammasome pathway.

Methods: Using house dust mite (HDM) and lipopolysaccharide (LPS), we induced a neutrophilic steroid hyporesponsive asthma mouse model to investigate the effect of vitamin D3 on downregulating the NLRP3 inflammasome pathway and enhancing steroid sensitivity.

Results: We showed that calcitriol, the active form of vitamin D3, could downregulate the NLRP3 inflammasome pathway. This was associated with a significant reduction in airway hyperresponsiveness, IL-17 release, neutrophil infiltration, and mucus secretion. Further, calcitriol enhanced steroid sensitivity by inhibiting the expression of GR-β. Mechanistically, calcitriol targeted the NLRP3 inflammasome to ubiquitination.

Conclusions: Our research highlights the potential use of calcitriol as a low cost and accessible supplement to ameliorate airway inflammation during severe steroid hyporesponsive asthma.

Objective and design: Airway remodelling (AR) is a disabling phenomenon in patients with severe asthma, yet suitable models are lacking. We previously developed a dog allergen-induced murine asthma model characterized by T2^low Th17-driven neutrophilic airway inflammation and AR. To assess its relevance to human AR associated with T2^low severe asthma, a condition characterised by poor response to inhaled steroids, we tested the steroid sensitivity of the key features of this model.

Material: Asthma was induced in C57BL/6 J mice by intranasal sensitization, followed by a three-week challenge with dog allergen.

Treatment: Daily intraperitoneal 1 mg kg^-1 dexamethasone was administrated during the last week of challenge.

Methods: We measured airway resistances in response to methacholine, cellular inflammation in bronchoalveolar lavage, lung cytokines, and quantified AR features, in response to dexamethasone.

Results: Dexamethasone-treated mice showed persistent airway hyperresponsiveness, neutrophilic inflammation, and Il17a overexpression, whereas Il22 expression was abrogated. Pathological AR features, including mucus hyperproduction, subepithelial fibrosis and smooth muscle hypertrophy were not eliminated by dexamethasone.

Conclusions: Our dog allergen-induced murine model of asthma mirrors the steroid-insensitive traits of human severe T2^low asthma with AR, making it a relevant tool for identifying novel therapeutic targets in this orphan asthma subset.