Mediators of Inflammation最新文献

{"title":"Inhibiting Tyrosine Kinase 2 Ameliorates Antiphospholipid Syndrome Nephropathy.","authors":"Kuo-Tung Tang, Yu-Sin Chen, Tzu-Ting Chen, Ya-Hsuan Chao, Shu-Ping Kung, Der-Yuan Chen, Chi-Chien Lin","doi":"10.1155/mi/5568822","DOIUrl":"10.1155/mi/5568822","url":null,"abstract":"<p><p><b>Objective:</b> Antiphospholipid antibody syndrome (APS) is an autoimmune disease characterized by the presence of <i>β</i>2-glycoprotein I (<i>β</i>2-GPI)-targeting antiphospholipid antibodies (aPLs) and vascular thrombosis or obstetrical complications. One of its severe manifestations is nephropathy. <b>Methods:</b> To examine the role of type I interferon (IFN) and therapeutic potential of tyrosine kinase 2 (Tyk2) inhibition, we administered BMS-986202, a novel Tyk2 inhibitor, in a mouse model of APS nephropathy. We administered BMS-986202 to BALB/c mice at a dose of 2 mg/kg. Biochemical and histological characteristics of APS nephropathy were then determined. The type I IFN signature in the kidney was also evaluated by real-time polymerase chain reaction (PCR). <b>Results:</b> The Tyk2 inhibitor reversed the elevation of blood urea nitrogen (BUN) and microalbuminuria in the murine model of APS nephropathy. In addition, the Tyk2 inhibitor reversed the pathological vascular changes in the kidney as judged in electron microscopy (EM), and fibrin and C3 deposition as revealed in immunohistochemistry (IHC). An increased expression levels of IFN signature (IFN regulatory factor 7 (IRF7) and Mx1) in the kidneys of APS mice were found. Tyk2 inhibition reversed such an upregulation. <b>Conclusion:</b> Our results demonstrated the key role of type I IFN in the pathogenesis of APS nephropathy. Furthermore, the therapeutic efficacy of Tyk2 inhibition was demonstrated in a murine model of APS nephropathy. Our results could provide a new treatment strategy for this debilitating disease.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"5568822"},"PeriodicalIF":4.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11688129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Inflammatory Factors, Nitric Oxide, and Arterial Stiffness Through Aquatic Walking for Amelioration and Disease Prevention: Targeting in Obese Elderly Women.","authors":"Woo-Hyeon Son, Woo-Min Jeong, In Young Park, Min-Seong Ha","doi":"10.1155/mi/5520987","DOIUrl":"10.1155/mi/5520987","url":null,"abstract":"<p><p>In elderly women, hormonal changes lead to elevated body fat content, which results in elevated levels of vascular inflammatory factors, thereby increasing the risk of cardiovascular diseases (CVDs) associated with endothelial dysfunction. Regular physical exercises tend to keep these in check and are protective to the body. Aerobic exercise has been reported to improve CVD in obese elderly women; in this regard, aquatic exercises have been demonstrated to be more efficient in energy metabolism than land-based exercise. This study aimed to examine the effect of aquatic walking exercises on the levels of inflammatory factors, nitric oxide (NO), and brachial-ankle pulse wave velocity (baPWV) in obese elderly women. We measured these in 26 obese elderly women who were randomly assigned to control (<i>n</i> = 12) and aquatic walking exercise (<i>n</i> = 14) groups. After subjecting them to aquatic walking exercises thrice a week for 12 weeks, we specifically found a significant reduction in IL-6 levels and an increase in NO levels in these obese elderly women. This was paralleled with a reduction in the right baPWV (baPWV-R). Together, these results indicate that aquatic walking exercises can help improve vascular inflammatory factors, NO levels, and arterial stiffness.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"5520987"},"PeriodicalIF":4.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation Between Neutrophil-Lymphocyte Ratio and Inhospital Cardiac Events in Geriatric Patients With Hip Fractures.","authors":"Miaomiao Yu, Zhen Cui, Ying Bai","doi":"10.1155/mi/5587265","DOIUrl":"10.1155/mi/5587265","url":null,"abstract":"<p><p><b>Background:</b> The novel inflammatory biomarker known as the neutrophil-lymphocyte ratio (NLR) has shown great potential in predicting and prognosing many diseases. However, its correlation with postoperative inhospital major adverse cardiac events (MACEs) in geriatric patients with hip fractures remains unclear. This study investigated the relationship between NLR and postoperative inhospital MACEs among geriatric patients with hip fractures. <b>Methods:</b> We enrolled geriatric patients with hip fractures who were hospitalized in the Department of Geriatric Traumatology and Orthopedics, Beijing Jishuitan Hospital, Capital Medical University, between January 2023 and November 2023. After surgery, the patients were transferred to the intensive care unit (ICU) for postoperative monitoring and treatment. Patients were assigned to the MACE or non-MACE group based on the occurrence of MACEs after surgery during their hospital stay. Clinical data were retrospectively analyzed. <b>Results:</b> In all, 216 patients were recruited into the study: 34 in the MACE group and 182 in the non-MACE group. Univariate and multivariate analyses revealed that a medical history of stroke (odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.18-6.01; <i>p</i>=0.018) and elevated preoperative NLR (OR = 1.09, 95% CI = 1.03-1.17; <i>p</i>=0.005) were significant risk factors for postoperative inhospital MACEs. The area under the curve (AUC) of preoperative NLR-predicted MACEs was 0.65 (0.55-0.75). Patients with a preoperative NLR <6.49 were less likely to experience inhospital MACEs, demonstrating a sensitivity of 61.8% and specificity of 64.8%. <b>Conclusion:</b> Elevated preoperative NLR is an independent risk factor for postoperative inhospital MACEs in geriatric patients with hip fractures.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"5587265"},"PeriodicalIF":4.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-Inducible Factor-1α Modulates the Toll-Like Receptor 4/Nuclear Factor Kappa B Signaling Pathway in Experimental Necrotizing Enterocolitis.","authors":"Yunfei Zhang, Mei Yan, Yingbin Yue, Yongfeng Cheng","doi":"10.1155/mi/4811500","DOIUrl":"10.1155/mi/4811500","url":null,"abstract":"<p><p>Necrotizing enterocolitis (NEC) is a devastating disease observed in premature infants, characterized by intestinal ischemia and inflammation. Hypoxia-inducible factor-1 alpha (HIF-1α), a master regulator of the cellular response to hypoxia and ischemia, plays a critical role in NEC pathogenesis. However, the precise mechanisms by which HIF-1α influences the intestines in NEC remain poorly understood. Herein, we aimed to explore the role of HIF-1α in NEC using a transgenic mouse model. We induced NEC in neonatal mice from postnatal day 5 to 9, and various parameters, including intestinal injury, oxidative stress, inflammatory responses, intestinal epithelial cell (IEC) proliferation, and apoptosis, were assessed. The results confirmed that the absence of intestinal epithelial HIF-1α increased the susceptibility of mice to NEC-induced intestinal injury, as evidenced by increased oxidative stress, inflammatory responses, apoptosis, and inhibition of proliferation. Additionally, we observed an upregulation of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway specifically in the intestines of mice lacking HIF-1α in IECs (HIF-1α^ΔIEC) with NEC. These findings provide crucial insights into the role of HIF-1α in regulating intestinal oxidative stress and inflammation to maintain intestinal homeostasis, highlighting its association with the TLR4-NF-κB signaling pathway. Furthermore, these insights might lead to the identification of novel therapeutic targets for the treatment of NEC.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"4811500"},"PeriodicalIF":4.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning and Mendelian Randomization Reveal Molecular Mechanisms and Causal Relationships of Immune-Related Biomarkers in Periodontitis.","authors":"Yuan Li, Bolun Zhang, Dengke Li, Yu Zhang, Yang Xue, Kaijin Hu","doi":"10.1155/mi/9983323","DOIUrl":"10.1155/mi/9983323","url":null,"abstract":"<p><p>This study aimed to investigate the molecular mechanisms of periodontitis and identify key immune-related biomarkers using machine learning and Mendelian randomization (MR). Differentially expressed gene (DEG) analysis was performed on periodontitis datasets GSE16134 and GSE10334 from the Gene Expression Omnibus (GEO) database, followed by weighted gene co-expression network analysis (WGCNA) to identify relevant gene modules. Various machine learning algorithms were utilized to construct predictive models, highlighting core genes, while MR assessed the causal relationships between these genes and periodontitis. Additionally, immune infiltration analysis and single-cell sequencing were employed to explore the roles of key genes in immunity and their expression across different cell types. The integration of machine learning, MR, and single-cell sequencing represents a novel approach that significantly enhances our understanding of the immune dynamics and gene interactions in periodontitis. The study identified 682 significant DEGs, with WGCNA revealing seven gene modules associated with periodontitis and 471 core candidate genes. Among the 113 machine learning algorithms tested, XGBoost was the most effective in identifying periodontitis samples, leading to the selection of 19 core genes. MR confirmed significant causal relationships between CD93, CD69, and CXCL6 and periodontitis. Further analysis showed that these genes were correlated with various immune cells and exhibited specific expression patterns in periodontitis tissues. The findings suggest that CD93, CD69, and CXCL6 are closely related to the progression of periodontitis, with MR confirming their causal links to the disease. These genes have potential applications in the diagnosis and treatment of periodontitis, offering new insights into the disease's molecular mechanisms and providing valuable resources for precision medicine approaches in periodontitis management. Limitations of this study include the demographic and sample size constraints of the datasets, which may impact the generalizability of the findings. Future research is needed to validate these biomarkers in larger, diverse cohorts and to investigate their functional roles in the pathogenesis of periodontitis.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"9983323"},"PeriodicalIF":4.4,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irisin Alleviates Cognitive Impairment by Inhibiting AhR/NF-<i>κ</i>B-NLRP3-Mediated Pyroptosis of Hippocampal Neurons in Chronic Kidney Disease.","authors":"Jialing Zhang, Xingtong Dong, Qi Pang, Aihua Zhang","doi":"10.1155/mi/2662362","DOIUrl":"10.1155/mi/2662362","url":null,"abstract":"<p><p><b>Introduction:</b> Cognitive impairment is a vital complication of chronic kidney disease (CKD). The effect of irisin on CKD-induced cognitive impairment remains unclear. In the present study, we aimed to investigate the role of Irisin in mitigating cognitive impairment and explore the underlying mechanisms in CKD. <b>Methods:</b> A CKD mice model was established by adenine. Cognitive function was assessed via the novel object recognition (NOR). Interleukin-1<i>β</i> (IL-1<i>β</i>) levels were measured by enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related protein expression was analyzed using western blotting. <b>Results:</b> Our data showed an upregulation of cell pyroptosis in hippocampus tissues of CKD mice, accompanied by significant cognitive impairment. Pyroptosis and cognitive impairment was both improved by Irisin treatment in vivo. Additionally, irisin markedly downregulated pyroptosis levels through aryl hydrocarbon receptor (AhR)/NF-<i>κ</i>B p65 signaling in HT-22 cells pretreated with indoxyl sulfate (IS). In vitro experiments further confirmed that pyroptosis was inhibited by AhR and NF-<i>κ</i>B p65 inhibitors. <b>Conclusions:</b> We first demonstrated that irisin alleviated cognitive impairment by inhibiting AhR/NF-<i>κ</i>B-NLRP3-mediated pyroptosis of hippocampal neurons in CKD. Overall, irisin may have the potential to serve as a critical antipyroptotic agent for improving CKD-induced cognitive impairment.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"2662362"},"PeriodicalIF":4.4,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin Alleviates the TNF-<i>α</i>-Induced Inflammatory Response of Human Microvascular Endothelial Cells via the Akt/MAPK/NF-<i>κ</i>B Pathway.","authors":"Qing-Yu Lu, Li Guo, Qi-Yun Zhang, Fu-Mei Yang, Shu-Ting Zhou, Qian-Yun Sun","doi":"10.1155/mi/6393872","DOIUrl":"10.1155/mi/6393872","url":null,"abstract":"<p><p>Endothelial dysfunction and pathological alterations are pivotal in the pathogenesis of cardiovascular disease. To date, effective interventions for these endothelial changes are lacking. Tumor necrosis factor-alpha (TNF-<i>α</i>) is known to significantly contribute to these alterations. It has been reported the potential of luteolin to mitigate TNF-<i>α</i>-induced inflammation, yet its specific mechanisms and targets still remain to be elucidated. This study aims to investigate the effects and mechanisms of luteolin on TNF-<i>α</i>-induced inflammatory injury in human microvascular endothelial cells, thereby advancing the understanding of luteolin's medicinal properties. Our findings demonstrate that luteolin notably inhibits TNF-<i>α</i>-induced phosphorylation of Akt, mitogen activated protein kinase (MAPK), and the nuclear factor-kappaB (NF-<i>κ</i>B) p65. It significantly reduces the transcriptional activity of NF-<i>κ</i>B p65 and AP-1 and decreases the expression of mRNA and proteins related to adhesion molecules and inflammatory mediators. Additionally, luteolin inhibited the reduction in STAT3 phosphorylation. In conclusion, luteolin effectively suppresses TNF-<i>α</i>-induced inflammatory injury in endothelial cells via the Akt/MAPK/NF-<i>κ</i>B pathway.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"6393872"},"PeriodicalIF":4.4,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Lactobacillus reuteri</i> Alleviates Hyperoxia-Induced BPD by Activating IL-22/STAT3 Signaling Pathway in Neonatal Mice.","authors":"Meiyu Zhang, Decai Li, Liujuan Sun, Yu He, Qingqing Liu, Yi He, Fang Li","doi":"10.1155/mi/4965271","DOIUrl":"10.1155/mi/4965271","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in preterm infants. Little is known about the regulatory effect of lung <i>Lactobacillus</i> and its mechanism in BPD. This study explored the effect of <i>L. reuteri</i> on hyperoxia-induced mice lung injuries and examined whether <i>L. reuteri</i> played a role via the IL-22/STAT3 pathway. We found that the intranasal administration of <i>L. reuteri</i> and its tryptophan metabolite indole-3-aldehyde (3-IAld) ameliorated hyperoxia-induced mice lung BPD-like changes, deceased proinflammatory cytokines (IL-1<i>β</i>, IL-6, and TNF-<i>α</i>), and increased the levels of surfactant-associated protein C (SPC), aquaporin 5 (AQP5), and vascular endothelial growth factor receptor 2 (VEGFR2, also known as FLK-1). Furthermore, <i>L. reuteri</i> and 3-IAld increased the expression of IL-22. IL-22 was also confirmed to ameliorate hyperoxia-induced mice lung pathological changes, and the protective effects of <i>L. reuteri</i> could be inhibited by anti-IL-22 neutralizing antibody. Finally, we confirmed STAT3 activation by IL-22 in MLE-12 cells. In summary, our study confirmed <i>L. reuteri</i> alleviated hyperoxia-induced lung BPD-like changes in mice by activating the IL-22/STAT3 signaling pathway via IL-22 production. Probiotics <i>Lactobacillus</i> is a potential treatment for hyperoxia-induced lung injury in newborns.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"4965271"},"PeriodicalIF":4.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide BG From Bitter Gourd (<i>Momordica Charantia</i>) Improves Adjuvant-Induced Arthritis by Modulating the Necroptosis/Neutrophil Extracellular Traps/Inflammation Axis and the Gut Microbiota.","authors":"Wenyan Han, Yanan Xu, Suyila Qimuge, Changshan Wang, Xiulan Su","doi":"10.1155/mi/1995952","DOIUrl":"10.1155/mi/1995952","url":null,"abstract":"<p><p><b>Background:</b> BG is a novel bioactive peptide derived from bitter gourd (<i>Momordica charantia</i>), known for its anti-inflammatory and immunomodulatory properties. In the present study, our objective is to investigate the functional roles and mechanisms of BG in the context of rheumatoid arthritis (RA). <b>Methods:</b> A rat model of adjuvant-induced arthritis (AIA) was established by administering complete Freund's adjuvant (CFA). The viability of BG-mediated AIA was evaluated by assessing changes in rat body weight, joint swelling, ankle joint pathology, inflammation, necroptosis, the formation of neutrophil extracellular traps (NETs), and gut microbiota. <b>Results:</b> The results of the study showed that peptide BG was effective in improving weight loss, joint swelling, serum IgM-rheumatoid factor (IgM-RF) level, and pathological injury of ankle joint in rats with AIA. BG administration resulted in a decrease in erythrocyte sedimentation rate, serum C-reactive protein (CRP), and inflammatory factor (interferon-<i>γ</i> (IFN-γ), interleukin-1<i>β</i> (IL-1<i>β</i>), and tumor necrosis factor-<i>α</i> (TNF-<i>α</i>)) in AIA rats. Additionally, the administration of CFA resulted in an increase in the protein levels of myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone H3 (CitH3), peptidyl arginine deiminase 4 (PAD4), p-mixed lineage kinase domain-like (p-MLKL), and cleaved caspase 8. However, this increase was found to be inhibited by BG treatment. Furthermore, it has been found that peptide BG possesses the capacity to regulate the species composition structure of the intestinal microbiota, thereby, facilitating the reestablishment of microbial diversity and equilibrium. <b>Conclusion:</b> Peptide BG has demonstrated efficacy in ameliorating AIA through its regulation of the necroptosis/NETs/inflammation axis and the gut microbiota. This finding underscores the potential of BG as a promising therapeutic intervention for RA.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"1995952"},"PeriodicalIF":4.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATG16L1 Depletion-Mediated Activation of the TRAF1 Signaling in Macrophages Aggravates Liver Fibrosis.","authors":"Yufeng Pan, Yi Wei, Xinyu Zhan, Qingfa Bu, Zibo Xu, Xiaozhang Xu, Qi Wang, Yuan Liang, Yue Yu, Haoming Zhou, Ling Lu","doi":"10.1155/mi/8831821","DOIUrl":"10.1155/mi/8831821","url":null,"abstract":"<p><p><b>Background:</b> Hepatic macrophages play an indispensable role in liver pathophysiology, serving as key orchestrators of both liver injury and repair processes. ATG16L1 (autophagy-related 16 like 1) has emerged as a novel and critical autophagy marker. In macrophages, ATG16L1 assumes a particularly crucial role. The current understanding of how macrophage ATG16L1 regulates liver inflammation in the context of liver fibrosis is unclear. <b>Methods:</b> This study included clinical patient samples of liver fibrosis and established a murine model with myeloid-specific <i>Atg16l1</i> knockout, creating a mouse model of liver fibrosis. Employing RNA sequencing, we sought to elucidate the mechanisms of macrophage ATG16L1 in liver fibrosis by identifying critical signaling pathways. To assess the influence of macrophage ATG16L1 on hepatocyte apoptosis and hepatic stellate cell (HSC) activation, we constructed a dedicated culture system. Ultimately, the introduction of mice with myeloid-specific <i>Atg16l1</i> knock-in substantiated the protective role of myeloid-specific <i>Atg16l1</i> against inflammatory signaling, hepatocyte apoptosis, and activation of HSCs. <b>Results:</b> An upregulation of the ATG16L1 signal was observed in the liver tissues of patients with liver fibrosis and in fibrotic mice, predominantly localized to hepatic macrophages. In <i>Atg16l1</i> ^Δ<i>Mφ</i> mice afflicted with liver fibrosis, we detected exacerbated liver damage, evidenced by heightened inflammatory signal expression, increased hepatocyte apoptosis, and enhanced activation of HSCs. The absence of macrophage <i>Atg16l1</i> was found to result in elevated TNF receptor-associated factor 1 (TRAF1) signaling, triggering inflammatory activation, intensifying hepatocyte apoptosis, and facilitating HSC activation through the transforming growth factor beta 1 (TGF-<i>β</i>1) signaling. The detrimental effects of macrophage <i>Atg16l1</i> depletion were demonstrated to be mitigated upon <i>Atg16l1</i> reintroduction. <b>Conclusions:</b> This research delved into the mechanisms by which the macrophage ATG16L1 signal influences inflammatory signaling, hepatocyte apoptosis, and activation of HSCs in liver fibrosis. Consequently, it offers theoretical substantiation and an experimental groundwork for the identification of biological targets for therapeutic intervention in liver fibrosis.</p>","PeriodicalId":18371,"journal":{"name":"Mediators of Inflammation","volume":"2024 ","pages":"8831821"},"PeriodicalIF":4.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11614508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}