Inflammation最新文献

Periodontitis, characterized by progressive alveolar bone destruction, leads to the loss of attachment and stability of the affected teeth. Macrophages, especially the proinflammatory M1 subtype, are key in periodontitis pathogenesis, driving the disease's inflammatory and destructive processes. Despite existing insight into their involvement, comprehensive understanding of the underlying molecular mechanisms remains limited. TRPV1 is a non-selective cation channel protein and is known to regulate cellular function and homeostasis in macrophages. Our research objective was to investigate the impact of TRPV1 on the proinflammatory attributes of M1 macrophages in periodontal tissues, exploring potential mechanistic pathways. A mouse model of periodontitis was established using Porphyromonas gingivalis inoculation and ligature application around the maxillary second molar. Immunohistological analysis showed a significant reduction in macrophage TRPV1 expression in periodontitis-induced mice. Treatment with capsaicin, a TRPV1 agonist, was observed to effectively elevate TRPV1 expression in these macrophages. Furthermore, micro-computed tomography analysis revealed a marked decrease in alveolar bone resorption in the capsaicin -treated group, compared with vehicle and healthy control groups. Our in vitro findings show that capsaicin treatment successfully attenuated LPS-induced TNF-α and IL-6 production in macrophages, mediated through NRF2 activation, consequently reducing intracellular ROS levels. These findings suggest that TRPV1 agonists, through modulating M1 macrophage activity and up-regulating TRPV1, could be a novel therapeutic approach in periodontal disease management.

Ferroptosis is a newly proposed form of programmed cell death that is iron-dependent and closely linked to oxidative stress. Its specific morphological changes include shrunken mitochondria, increased density of mitochondrial membrane, and rupture or disappearance of mitochondrial cristae. The main mechanism of ferroptosis involves excessive free iron reacting with membrane phospholipids, known as the Fenton reaction, resulting in lipid peroxidation. However, the role of iron in acute lung injury (ALI) remains largely unknown. In this study, LPS was instilled into the airway to induce ALI in mice. We observed a significant increase in iron concentration during ALI, accompanied by elevated levels of lipid peroxidation markers such as malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE). Treatment with the iron chelator deferoxamine (DFO) or ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed lipid peroxidation and significantly attenuates lung injury. Similarly, DFO or Fer-1 treatment improved the cell survival significantly in vitro. These results demonstrated that ferroptosis occurs during ALI and that targeting ferroptosis is an effective treatment strategy. Interestingly, we found that the increased iron was primarily concentrated in mitochondria and DFO treatment effectively restored normal mitochondria morphology. To further confirm the damaging effect of iron on mitochondria, we performed mitochondrial stress tests in vitro, which revealed that iron stimulation led to mitochondrial dysfunction, characterized by impaired basal respiratory capacity, ATP production capacity, and maximum respiratory capacity. MitoTEMPO, an antioxidant targeting mitochondria, exhibited superior efficacy in improving iron-induced mitochondrial dysfunction compared to the broad-spectrum antioxidant NAC. Treatment with MitoTEMPO more effectively alleviated ALI. In conclusion, ferroptosis contributes to the pathogenesis of ALI and aggravates ALI by impairing mitochondrial function.

RNA binding proteins (RBPs) have the potential for transcriptional regulation in sepsis-induced liver injury, but precise functions remain unclear. Our aim is to conduct a genome-wide expression analysis of RBPs and illuminate changes in the regulation of alternative splicing in sepsis-induced liver injury. RNA-seq data on "sepsis and liver" from the publicly available NCBI data set was analyzed, and differentially expressed RBPs and alternative splicing events (ASEs) in the healthy and septic liver were identified. Co-expression analyses of sepsis-regulated RBPs and ASEs were performed. Models of sepsis were established to validate hepatic RBP gene expression patterns with different treatments. Pairwise analysis of gene expression profiles of sham, cecum ligation puncture (CLP), and CLP with dichloroacetate (CLPDCA) mice allowed 1208 differentially expressed genes (DEGs), of which 800 were up-regulated and 408 down-regulated, to be identified. DEGs were similar in both Sham and CLPDCA mice. The KEGG analysis showed that up-regulated genes as being involved in cytokine-cytokine receptor interaction and IL-17 signaling pathway and down-regulated genes in metabolic pathways. Differences in lipid metabolism-related alternative splicing events, including A3SS, were also found in CLP and CLPDCA compared with sham mice. Thirty-seven RBPs, including S100a11, Ads2, Fndc3b, Fn1, Ddx28, Car2, Cisd1, and Ptms, were differentially expressed in CLP mice and the regulated alternative splicing genes(RASG) with the RBP shown to be enriched in lipid metabolic and oxidation-reduction-related processes by GO functional analysis. In KEEG analysis the RASG mainly enriched in metabolic pathway. The models of sepsis were constructed with different treatment groups, and S100a11 expression in the CLP group found to be higher than in the sham group, a change that was reversed by DCA. The alternative splicing ratio of Srebf1 and Cers2 decreased compared with the sham group increased after DCA treatment. Abnormal profiles of gene expression and alternative splicing were associated with sepsis-induced liver injury. Unusual expression of RBPs, such as S100a11, may regulate alternative splicing of lipid metabolism-associated genes, such as Srebf1 and Cers2, in the septic liver. RBPs may constitute potential treatment targets for sepsis-induced liver injury.

Resatorvid (TAK-242), a specific inhibitor of Toll-like receptor-4 (TLR4), has attracted attention for its anti-inflammatory properties. Despite this, few studies have evaluated its effects on ulcerative colitis (UC). This study aimed to investigate the effects of TAK-242 on macrophage polarization and T helper cell balance and the mechanism by which it alleviates UC. Our findings indicated that TLR4 expression was elevated in patients with UC, a mouse model of UC, and HT29 cells undergoing an inflammatory response. TAK‑242 treatment reduced apoptosis in TNF-α and LPS-stimulated HT29 cells and alleviated symptoms of dextran sulfate sodium (DSS)‑induced colitis in vivo. TAK‑242 downregulated TLR4 expression and decreased the secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β while enhancing IL-10 production. TAK-242 also reduced M1 macrophage polarization and diminished Th1 and Th17 cell infiltration while increasing Th2 cell infiltration and M2 macrophage polarization both in vitro and in vivo. Mechanistically, TAK-242 inhibited the JAK2/STAT3 signaling pathway, an important regulator of macrophage polarization and T helper cell balance. Furthermore, the in vivo and in vitro effects of TAK-242 were partially negated by the administration of the JAK2/STAT3 antagonist AG490, suggesting that TAK-242 inhibits the JAK2/STAT3 pathway to exert its biological activities. Taken together, this study underscores TAK-242 as a promising anti-UC agent, functioning by modulating macrophage polarization and T helper cell balance via the TLR4/JAK2/STAT3 signaling pathway.

Periodontitis is a chronic inflammatory disease strongly influenced by host's immune response. Aberrant sialylation on cell surface plays a key role in inflammation and immunity. This study aims to identify sialylation-related genes associated with periodontitis and explore their impact on periodontal immune microenvironment. Differential expression analysis and machine learning were employed to determine core sialylation-related genes after datasets were retrieved and integrated. A diagnostic model incorporating these genes was constructed, following the immune cell infiltration analysis. Consensus clustering and weighted gene co-expression network analysis stratified periodontitis patients into subgroups and identified associated module genes. Single-cell sequencing data was further utilized to investigate the impact of sialylation on the periodontal immune microenvironment with pseudo-time series analysis and cell communication analysis. Periodontitis had a higher sialylation score with six key sialylation genes (CHST2, SELP, ST6GAL1, ST3GAL1, NEU1, FCN1) identified. The multi-gene diagnostic model demonstrated high accuracy and efficacy. Significant associations were observed between the key genes and immune cell populations, such as monocytes and B cells, in the periodontal immune microenvironment. Clustering analysis revealed two distinct sialylation-related subgroups with differential immune profiles. Single-cell data showed a significantly higher expression of sialylation-related genes in monocytes, which was found to significantly impact their developmental processes as well as their intercellular communication with B cells. The six identified sialylation-related genes hold potential as periodontitis biomarkers. High sialylation expression can impact the differentiation and cell-cell communication of monocytes. Sialylation-related genes are closely associated with alterations in the periodontal immune microenvironment.

Macrophages in smoking environment exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow nicotine to "educate" macrophages are incompletely understood. Here, we identified that nicotine transiently activates and subsequently deactivates monocytes, leading to reduced anti-infective capability of macrophages. This deactivation results in a suppression of IL-17-producing cell expansion through decreased IL-1β production. Mechanistically, nicotine induces the expression of IRAK-M in macrophages, which inhibits NF-κB signaling and restrains NLRP3 inflammasome-mediated IL-1β production. Moreover, the induction of IRAK-M by nicotine is mediated through α7 nAChR binding, which activates downstream STAT3 and AKT signaling pathways. Targeting the interaction between nicotine and α7 nAChR can decrease IRAK-M expression and restore LPS-mediated NLRP3 inflammasome-driven IL-1β production. Collectively, these findings elucidate how nicotine modulates macrophage function through complex signaling mechanisms, ultimately impacting their anti-infective responses and inflammatory processes.

Artemisinin and its derivatives, used as front-line anti-malarial drugs, exhibit anti-inflammatory properties. They were found to suppress the generation and function of Th1 and Th17 cells while promoting the generation of Foxp3 + regulatory T cells (Tregs). However, the specific role of Artemotil (β-arteether) in modulating the generation and functions of CD4 + T cells, particularly Type 1 regulatory T cells (Tr1), remains to be explored. Tr1 cells are one of the key cell types that are essential for regulating inflammatory response through IL-10. In this study, we report that Artemotil selectively promotes generation of Tr1 cells induced by IL-27 by upregulating signature genes of Tr1 cells, such as c-Maf, AhR, prdm1, IRF-1, and Batf, while inhibiting the Th1, Th2, and Th17 cells generation. We found that co-administration of Artemotil with anti-CD3 antibody increases the induction of IL-10 and frequency of Tr1 cells while suppressing Th1 and Th17 cells in vivo. Artemotil suppresses T-cell-induced enteropathy and alleviates the signs of colitis associated with the increased frequencies of Tr1 cells. Taken together, our data suggest that Artemotil provides protection in T-cell-mediated colitis by increasing the expansion of Tr1 cells and inhibiting the generation of Th1 and Th17 cells.

IL-17A is a potent proinflammatory cytokine that plays a crucial role in the pathogenesis of various lung diseases. This study focused on the evaluation of the role of IL-17 receptor signaling through one-week intranasal exposure of IL-17A in lung tissues of BALB/c mice. IL-17A triggered inflammatory responses in the mice lungs and led to changes in the morphological alveolar arrangements. Exposure of IL-17A induced redox imbalance by triggering an increase in the level of the pro-oxidants (reactive oxygen species, nitrite and malondialdehyde) and reduction of the levels of antioxidant proteins (glutathione, superoxide dismutase and catalase) in the lung tissue. IL-17A also caused a significant elevation in the levels of proinflammatory cytokines lines including TNF-α, IL-1β and IL-6, in lung tissue as well as in plasma. More interestingly, these changes were accompanied by the alterations in IL-17 receptor downstream signaling through activation of IL-17R-Act1-TRAF6-IKBα-mediated pathway. IL-17A exposure also caused lung tissue injury, recruitment and polarization of immune cells from anti-inflammatory to pro-inflammatory. This study clearly demonstrated the role of IL-17A-induced signaling in worsening lung inflammatory diseases, and hence points towards its emergence as an important therapeutic target to control lung inflammation.

Numerous chemotherapeutic medications can have hazardous effects on the lungs, which can result in severe lung diseases. Methotrexate (MTX) is prescribed for cancer and inflammation-related disorders; nevertheless, it is exceptionally highly toxic and has multiple kinds of adverse reactions, including pulmonary injury. Our work was designed to demonstrate the ability of etoricoxib (ETO) to mitigate MTX-induced lung injury in experimental animals. Adult male Wistar rats were separated into four groups. The first group consisted of healthy controls that received carboxymethyl cellulose (1 ml/day, p.o.), the second group received a single dose of MTX (20 mg/kg/day, i.p.), the third group received ETO (10 mg/kg/day, p.o.) for three weeks, and the fourth group first received a single MTX (20 mg/kg, i.p.) and then was treated with ETO for three weeks. Concomitant treatment with ETO and MTX improved the histological structure of the lung tissue. It significantly altered the levels of oxidant/antioxidant markers, such as malondialdehyde (MDA), heme oxygenase-1 (HO-1), reduced glutathione (GSH), and nuclear factor erythroid 2-related factor 2 (Nrf-2), in favor of antioxidants. Moreover, ETO can normalize the proinflammatory cascade, which includes tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). At the molecular level, ETO downregulated the protein expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), and p38 mitogen-activated protein kinase (p38 MAPK) in inflamed rat lungs. In conclusion, our findings indicate that oral administration of ETO ameliorates MTX-induced lung injury by inhibiting oxidative stress and suppressing the TLR4/NF-κB and TLR4/p38-MAPK inflammatory signaling pathways.

Sappanone A (SAP), a high-isoflavone compound derived from the traditional Chinese medicine Sumu, exhibits various pharmacological activities, including anti-inflammatory and anti-oxidant effects. However, its protective effects on the liver have rarely been reported. The aim of this study was to investigate the effects of SAP on immune-mediated liver injury induced by concanavalin A (Con A) in mice and to explore the underlying molecular mechanisms. Mice were administered SAP intraperitoneally (50 mg/kg body weight). Three hours later, Con A (18 mg/kg) was injected via the tail vein to induce liver damage. Livers and blood were collected 12 h after Con A challenge. Liver cell apoptosis, oxidative stress, and M1 macrophage activation in vivo were investigated. Bone marrow-derived macrophages were used to confirm the effects of SAP on M1 polarization in vitro. The results indicated that SAP decreased transaminase levels, inhibited apoptosis, and improved oxidative stress in mouse livers. Furthermore, SAP significantly reduced the proportion of macrophages, inhibited the expression of CD86, and downregulated the expression of M1 macrophage-related inflammatory cytokines. Moreover, SAP-treated macrophages alleviated liver damage caused by Con A compared to non-SAP-treated macrophages. Mechanistically, SAP inhibited the phosphorylation of key molecules in the MAPK and NF-κB signaling pathways in macrophages, resulting in an inhibitory effect on M1 macrophage activation. Taken together, SAP alleviates immune-mediated liver injury induced by Con A by suppressing M1 macrophage polarization, which is partially associated with NF-κB and MAPK signaling pathways.