ImmunoTargets and Therapy最新文献

{"title":"A High-Throughput, Three-Dimensional Multiple Myeloma Model Recapitulating Tumor-Stroma Interactions for CAR-Immune Cell-Mediated Cytotoxicity Assay.","authors":"Sudjit Luanpitpong, Montira Janan, Jirarat Poohadsuan, Napachai Rodboon, Parinya Samart, Sasitorn Rungarunlert, Surapol Issaragrisil","doi":"10.2147/ITT.S503984","DOIUrl":"10.2147/ITT.S503984","url":null,"abstract":"<p><strong>Background: </strong>Multiple myeloma (MM) is characterized by an excessive proliferation of clonal plasma cells in the bone marrow (BM). Components in BM niche contribute to the immunosuppressive tumor microenvironment (TME), but three-dimensional (3D) MM models that recreate the complex TME and enable high-throughput cytotoxicity assay of chimeric antigen receptor (CAR)-engineered immune cells are still lacking.</p><p><strong>Methods: </strong>Stable, luciferase (Luc)-labeled target MM cells were generated using Luc/RFP dual reporter system to track MM growth. 3D spheroids were formed in a 96-well plate in the presence or absence of cancer-associated fibroblast (CAF)-like stromal cells activated by MM-derived conditioned medium and the cytotoxicity of CAR-immune cells, which were represented by third-generation anti-CD138 CAR-NK-92 cells, was evaluated by luciferase assay using a multimode microplate reader. Immune cell infiltration was visualized under a fluorescence microscope by using multiple fluorescent dyes.</p><p><strong>Results: </strong>We first showed that luciferase assay provides a relatively simple and robust means to specifically monitor Luc-labeled tumor cell growth in a coculture system, allowing the high-throughput assessment of CAR-immune cytotoxicity. Through this assay, we demonstrated that CAF-like stromal cells impaired NK cell effector function in 2D culture and 3D spheroids, likely via paracrine signaling and physical barrier function. Importantly, we showed that 3D spheroids consisting of MM cells and CAF-like stromal cells provide a more comprehensive, physiologically relevant immuno-oncology model. Our established model could also be used to investigate the trafficking and infiltration of immune cells into the core of spheroids. Herein, we showed that CAR incorporation did improve the ability of NK cells to infiltrate 3D spheroids.</p><p><strong>Conclusion: </strong>Our established 3D spheroid model, which partially recapitulates the complex TME with immunosuppressive environment, is suitable for high-throughput screening of CAR-immune cytotoxicity and could be important in accelerating immuno-oncology drug discovery for MM since there is a pressing need to establish innovative CAR-immune cells.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"321-338"},"PeriodicalIF":6.2,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Immunotherapy Targeting B7-H3: From Mechanisms to Clinical Applications.","authors":"Yining Guo, Xudong Wang, Chen Zhang, Weiwu Chen, Yutian Fu, Yanlan Yu, Yicheng Chen, Tiejuan Shao, Jie Zhang, Guoqing Ding","doi":"10.2147/ITT.S507522","DOIUrl":"10.2147/ITT.S507522","url":null,"abstract":"<p><p>B7-H3 (CD276) is an immune checkpoint from the B7 family of molecules and is abnormally expressed in tumor cells as a co-inhibitory molecule to promote tumor progression. Within the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing the T cell response, driving the polarization of tumor-associated macrophages (TAMs) to M2 phenotype, and inhibiting the function of other immune cells. In addition, B7-H3 promotes tumor cell proliferation, migration, invasion, metabolism disorder, angiogenesis, and resistance to treatment to promote tumor progression through its non-immunological functions. Immunotherapy targeting B7-H3, as well as combinations with other immune checkpoint therapies, have shown certain efficacy. In this review, we synthesizes the expression of B7-H3 and its mechanism to promote tumor progression through inducing immunomodulation and non-immunological functions, as well as its role of B7-H3 in tumor therapy, aiming to provide a reference for the clinical treatment of tumors.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"291-320"},"PeriodicalIF":6.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal Association Between Circulating Inflammatory Proteins and Autoimmune Liver Disease: a Bidirectional Two-Sample Mendelian Randomization Study.","authors":"Lina Leng, Ying Li, Tao Xu, Jingfang Shen, Lianju Li, Xiaoli Li","doi":"10.2147/ITT.S508140","DOIUrl":"10.2147/ITT.S508140","url":null,"abstract":"<p><strong>Introduction: </strong>To investigate whether there is a direct causal relationship between circulating inflammatory proteins and autoimmune liver disease (AILD).</p><p><strong>Materials and methods: </strong>We collected genetic data for various AILD from the Genome Wide Association Studies (GWAS) dataset. The latest research provides GWAS data for 91 proteins associated with inflammation. Perform bidirectional two sample Mendelian randomization (MR) analysis using inverse variance weighted (IVW) to determine the causal relationship between inflammatory proteins and AILD, and use Mendelian randomization Egger method (MR Egger), weighted median (WM), and weighted mode as supplementary evaluations. In addition, we conducted sensitivity analysis.</p><p><strong>Results: </strong>Positive MR analysis showed that CDCP1 (OR=1.363, p=0.0465) and IL-18 (OR=1.416, p=0.0477) were associated with higher including autoimmune hepatitis (AIH) risk. Higher CXCL11 (OR=1.574, p=9.23×10-5) were associated with an increased risk of primary biliary cholangitis (PBC). Lower levels of three inflammatory proteins were associated with increased risk of PBC. TNFSF12 (OR=1.827, p=0.0001, p_adj_fdr=0.0063), CD6 isoform (OR=1.126, p=0.0389), CCL20 (OR=1.880, p=0.0395) are associated with increased risk of primary sclerosing cholangitis (PSC). Reverse MR imaging showed that PBC may promote the expression levels of CCL4 (OR=1.023, p=0.0201) and OSM (OR=1.022, p=0.0236). PSC may promote the expression of five inflammatory proteins. Sensitivity analysis further excluded the effects of heterogeneity and horizontal pleiotropy.</p><p><strong>Conclusion: </strong>This study indicates a potential association between circulating inflammatory proteins and AILD, which may become a new diagnostic indicator or drug target for clinical application in the prevention and treatment of AILD. However, further investigation is needed.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"279-289"},"PeriodicalIF":6.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysyl Oxidase-Like 1 (LOXL1) Up-Regulation in Chondrocytes Promotes M1 Macrophage Activation in Osteoarthritis via NF-κB and STAT3 Signaling.","authors":"Yuyun Jiang, Shang Wang, Wei Zhu, Xi Liu, Yanwei Yang, Liyue Huo, Jixian Ye, Yongbin Ma, Yuepeng Zhou, Zhe Yang, Jiahui Mao, Xuefeng Wang","doi":"10.2147/ITT.S512768","DOIUrl":"10.2147/ITT.S512768","url":null,"abstract":"<p><strong>Purpose: </strong>Osteoarthritis (OA) constitutes a widespread degenerative joint disease predominantly affecting the elderly, leading to disability. There is still a lack of biomarkers for OA, so it cannot be intervened in time.</p><p><strong>Methods: </strong>OA biomarkers were identified from human cartilage datasets using LASSO and SVM-RFE, followed by ROC analysis. LOXL1 was prioritized for further research due to its high expression in OA cartilage and robust predictive performance. Anterior cruciate ligament transection (ACLT) surgery-induced OA rats were used to explore the correlation between LOXL1 and inflammatory factors and macrophages. Macrophage markers and cytokine secretion were detected from macrophages treated with LOXL1, or co-cultured with chondrocytes after LOXL1 siRNA silencing.</p><p><strong>Results: </strong>Five hub biomarkers with OA-specific expression were identified. Elevated LOXL1 correlated with IL-6 and IL-8 in patients and increased M1 macrophages in OA rats. LOXL1-stimulated macrophages upregulated CD86 and inflammatory cytokines. Silencing LOXL1 in chondrocytes reduced CD86, inflammatory cytokines, and NF-κB p65 and p-STAT3 expression in co-cultured macrophages, mitigating MMP13 and chondrocyte apoptosis. STAT3 and NF-κB signal inhibition reduces p-STAT3, p-p65, CD86, IL-6 and IL-1β expression in LOXL1-stimulated macrophages.</p><p><strong>Conclusion: </strong>This study underscores the pivotal role of LOXL1 in activating M1 macrophages through NF-κB and STAT3 signaling, thereby promoting pro-inflammatory cytokine secretion and contributing to OA pathogenesis. LOXL1 holds promise as a potential marker for early diagnosis of OA inflammation and as a novel therapeutic target.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"259-278"},"PeriodicalIF":6.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid Cells in the Immunosuppressive Microenvironment as Immunotargets in Osteosarcoma.","authors":"Cyrus J Sholevar, Natalie M Liu, Tasneem Mukarrama, Jinhwan Kim, Jessica Lawrence, Robert J Canter","doi":"10.2147/ITT.S485672","DOIUrl":"10.2147/ITT.S485672","url":null,"abstract":"<p><p>Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"247-258"},"PeriodicalIF":6.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Association Between Immune Cell Phenotypes and Osteoporosis Mediated by Inflammatory Cytokines: Insights from GWAS and Single-Cell Transcriptomics.","authors":"Shouxiang Kuang, Xiaoqing Ma, Lipeng Sun, Chang Wang, Yang Li, Guodong Wang, Jianmin Sun, Fengge Zhou, Chenggui Zhang","doi":"10.2147/ITT.S510102","DOIUrl":"10.2147/ITT.S510102","url":null,"abstract":"<p><strong>Background: </strong>Patients with osteoporosis experience increased fracture risk and decreased quality of life, which pose significant health burdens and financial challenges. Despite established links between immune cell phenotypes and inflammatory cytokines and osteoporosis, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment.</p><p><strong>Methods: </strong>Here, we performed a two-sample Mendelian randomization (MR) study to estimate the causal effects between 731 immune cell types, 91 and 41 inflammatory factors (which may have some overlap), and 5 types of osteoporosis. In subsequent mediation MR analysis, we assessed whether these inflammatory cytokines mediate the causal relationship between immune cell phenotypes and osteoporosis. Additionally, colo- calization analysis was performed using Bayesian colocalization. Single-cell transcriptomic analysis was performed using datasets from osteoporosis patients available in the Gene Expression Omnibus (GEO) database. Subsequently, single-cell sequencing analysis was performed, including dimensionality reduction, clustering, and pathway enrichment, to investigate the underlying mechanisms. Finally, to confirm the critical role of IgD⁺CD24⁺ B cells and IL-17C in osteoporosis, we established vivo dexamethasone-induced osteoporosis model. Micro-CT was used to assess the effectiveness of model establishment. Flow cytometry was performed to determine the proportion of IgD⁺CD24⁺ B cells within lymphocytes in the blood. ELISA and Western blotting were used to measure IL-17C levels in serum and bone tissue. Immunohistochemistry was conducted to evaluate the expression of IL-17C in bone tissue.</p><p><strong>Results: </strong>This study found that 32 immune cell phenotypes and 38 inflammatory cytokines were significantly associated with osteoporosis. Mediation analysis indicated that IgD+ CD24+ B cells exacerbated the risk of osteoporosis by influencing the levels of interleukin-17C (IL-17C). The mediated effect was 0.07837, accounting for 15.5% of the total effect. Single-cell transcriptome analysis supported that IgD+ CD24+ B cells play a key role in musculoskeletal-related pathways in osteoporosis patients. Additionally, we have demonstrated the significant involvement of IgD⁺CD24⁺ B cells and IL-17C in the osteoporosis disease model.</p><p><strong>Conclusion: </strong>Inflammatory cytokines play a crucial role in the pathogenesis of immunity-related osteoporosis. In particular, IgD+ CD24+ B cell %lymphocyte increase the risk of osteoporosis by modulating the levels of interleukin-17C. Our results provide evidence to support the link between immunity and osteoporosis and offer new therapeutic strategies for targeting inflammatory pathways in immune-mediated osteoporosis.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"227-246"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conversion of T Effector Cells Into T Regulatory Cells in Type 1 Diabetes/Latent Autoimmune Diabetes of Adults by Inhibiting eIF5A and Notch Pathways.","authors":"Shafiya Imtiaz Rafiqi, Ahmad Aldasouqi, Rodis D Paparodis, Sandesh Dewan, Aneeba Farooqi, Sarah Faisal, Yousuf Nemat, Nancy Salim, Salauddin Qureshi, Asif Mahmood, Yara Tovar, John Y Jun, Andrea L Kalinoski, Raghavendra G Mirmira, Juan Carlos Jaume, Shahnawaz Imam","doi":"10.2147/ITT.S504555","DOIUrl":"10.2147/ITT.S504555","url":null,"abstract":"<p><strong>Background: </strong>The generation of functionally active, stable T regulatory cells (Tregs) is a crucial target of type 1 diabetes (T1D) immunotherapy. This study investigated therapeutic intervention for T1D/Latent autoimmune diabetes in adults (LADA), wherein the diabetogenic proinflammatory Treg (intermediate) cell subset was characterized and driven to a Treg phenotype (CD4⁺CD25⁺FOXP3⁺). This involved simultaneous inhibition of the eukaryotic initiation factor 5a (eIF5a) and Notch pathways using GC7 (N1-Guanyl-1,7-diaminoheptane) and Anti-DLL4 (Delta-like-ligand-4).</p><p><strong>Methods: </strong>Peripheral blood from patients with T1D/LADA and healthy adults (n=7 each) was used to isolate the CD4⁺CD25^- T cell population and CD4 deficient peripheral blood mononuclear cells (PBMCs). Cells were subjected to GAD65+GC7+anti-DLL4 treatment for seven days and compared with conventional anti-CD3/CD28/CD137 stimulation for conversion into the Tregs. Newly plasticized Tregs were assessed for their suppressive potential against freshly isolated autologous T responder cells. In addition, live, dead, and apoptotic cell counts were performed to evaluate the adverse effects of immunomodulatory treatment on immune cells. The data was analyzed with GraphPad Prism using 1- or 2-way ANOVA and a Student's <i>t</i>-test.</p><p><strong>Results: </strong>A unique population of proinflammatory cytokines expressing intermediate Tregs (CD4⁺CD25^-IFNg⁺IL17⁺FOXP3⁺) was characterized in T1D/LADA patients and found significantly increased compared to age-matched healthy adults. Simultaneous inhibition of eIF5a and Notch pathways could induce Treg phenotype in Treg-deficient CD4⁺ T cells and CD4 deficient PBMCs from T1D/LADA patients. GAD65+GC7+anti-DLL4 treatment plasticized Tregs withstanding a proinflammatory milieu mimicking T1D/LADA, and the plasticized Tregs exhibited a stable and suppressive functional phenotype. Furthermore, GAD65+GC7+anti-DLL4 treatment had no adverse effects on immune cells.The present approach is a multipronged approach involving the inhibition of eIF5a and Notch pathways that addresses the upregulation of immune tolerance, differentiation, and proliferation of cytotoxic T cells and alleviates β-cell dysfunction. Additionally, this treatment strategy could also be leveraged to boost Treg generation following islet transplantation or as a combinational therapy along with adoptive cell transfer.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"205-226"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Characterization of 4A7: A High-Affinity Monoclonal Antibody Targeting Claudin18.2.","authors":"Yahui Wu, Juan Tian, Yangyihua Zhou, Ran Zhang, Xiang Gao, Longlong Luo","doi":"10.2147/ITT.S494696","DOIUrl":"https://doi.org/10.2147/ITT.S494696","url":null,"abstract":"<p><strong>Purpose: </strong>Claudin18.2 has emerged as a promising therapeutic target due to its high expression in gastric (GC) and pancreatic cancers (PC). However, patients with advanced, unresectable, or metastatic GC or PC face poor prognoses, highlighting the urgent need for more effective Claudin18.2-targeted therapies.</p><p><strong>Methods and results: </strong>We developed 4A7, a fully human monoclonal antibody with superior affinity and specificity for Claudin18.2, using a rigorous positive and negative screening strategy to eliminate cross-reactivity with Claudin18.1. In vitro, 4A7 demonstrated significantly enhanced binding activity, as well as robust antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), outperforming IMAB362, a clinical investigational antibody. In vivo, 4A7 exhibited remarkable tumor growth inhibition both as a monotherapy and in combination with anti-mPD-1, achieving superior efficacy compared to IMAB362. Additionally, 4A7 demonstrated a higher degree of humanization and comparable stability, supporting its translational potential.</p><p><strong>Conclusion: </strong>4A7 shows great promise as a next-generation therapeutic for Claudin18.2-positive cancers, offering improved efficacy and reduced immunogenicity. This study not only highlights 4A7's potential to address unmet clinical needs but also provides a foundation for future innovations in monoclonal antibody-based cancer therapy.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"189-203"},"PeriodicalIF":6.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting Causal Relationship Among Immune Cells, Plasma Metabolites and Coronary Atherosclerosis: A Mendelian Randomization Study.","authors":"Qi Cao, Jiajing Liu, Jingyu Sun, Shuangshuang Qian, Junhuai Song, Haoyang Zheng, Jinkun Wen, Bin Zheng","doi":"10.2147/ITT.S508042","DOIUrl":"10.2147/ITT.S508042","url":null,"abstract":"<p><strong>Background: </strong>Circulating immune cells and metabolites are linked to coronary atherosclerosis, but the specific causal relationships and the role of metabolites as mediators remain unclear.</p><p><strong>Methods: </strong>Summary statistics from GWAS datasets on immune cells (n=3,757), circulating metabolites (n=8,299), and coronary atherosclerosis (cases n=51,589; controls n=343,079) were analyzed using bidirectional Mendelian randomization. Two-step and multivariate Mendelian randomization were employed to identify mediating metabolites, with inverse variance weighting (IVW) as the primary method.</p><p><strong>Results: </strong>We identified nine immune cell phenotypes, including specific T-cell and monocyte populations, with significant causal links to coronary atherosclerosis. Additionally, 41 plasma metabolites across four metabolic pathways were identified, including 3-hydroxy-2-ethylpropionate and trans-2-hexenoylglycine. Mediation analysis revealed that 3-hydroxy-2-ethylpropionate mediated the effect of IgD+ CD24+ B-cells on coronary atherosclerosis (mediating effect: 0.961; 95% CI: 0.955-0.967), while trans-2-hexenoylglycine regulated IgD+ CD24+ B-cells, showing a mediation ratio of 16.7% (mediating effect: 0.983; 95% CI: 0.981-0.986).</p><p><strong>Conclusion: </strong>Key immune cell phenotypes and plasma metabolites were linked to coronary atherosclerosis. The roles of 3-hydroxy-2-ethylpropionate and trans-2-hexenoylglycine in regulating B-cell function suggest potential therapeutic targets for prevention and treatment.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"175-188"},"PeriodicalIF":6.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of M2 Macrophages-Derived Exosomes on Urethral Fibrosis and Stricture in Scar Formation.","authors":"Xiang Ren, Zhixian Wang, Jing Wang, Xing Li, Huizhi Wei, Chang Liu, Shiliang Liu, Yunpeng Zhu, Chunxiang Feng, Yisheng Yin, Yiqun Tian, Minglong Wu, Xiaoyong Zeng","doi":"10.2147/ITT.S500499","DOIUrl":"10.2147/ITT.S500499","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are highly plastic cells, and macrophage-derived exosomes (M-Exos) have been implicated in inflammation-related pathophysiologies, such as tissue injury and fibrosis repair. This study aimed to investigate the possible effects of M-Exos on the initiation and development of urethral fibrosis and stricture after injury, and to elucidate the underlying mechanisms.</p><p><strong>Methods: </strong>In this study, we used time-tracking immunofluorescence staining for M1 and M2 macrophage markers to characterize sequential properties in the site of injured urethra. Next, we harvested these exosomes from different macrophages to co-culture with fibroblasts to further confirm the role of exosome-mediated M2 macrophage-fibroblast communication. Then, high-throughput micro-RNA (miRNA) sequencing was performed to detect the candidate exosomal miRNA and its target gene. Furthermore, fibroblasts were transfected with mRFP-GFP-LC3 plasmid to detect the autophagy role of SIRT1 in the urethral fibroblasts fibrogenesis.</p><p><strong>Results: </strong>Here we found that M2-polarized macrophages triggered and dominated the fibrotic scene, purified exosomes from M2 macrophages exacerbated urethral fibroblast fibrogenesis, and the inhibition of exosome secretion abolished fibroblast fibrogenesis. Moreover, miR-34a-5p, which is highly enriched and packaged within M2-Exos, can be transferred from M2 macrophages into urethral fibroblasts, resulting in deterioration of proliferation and fibrogenesis. Mechanistically, M2-Exos miR-34a-5p could directly interact with the 3'-UTR of SIRT1, thereby suppressing SIRT1 expression in fibroblasts, leading to the blockage of autophagosome-lysosome fusion to impair urethral fibroblast autophagy flux and further exacerbate fibrogenesis. More importantly, repression of miR-34a-5p in M2-Exos mitigated-urethral strictures in rats with damaged urethra.</p><p><strong>Conclusion: </strong>M2 macrophage-derived exosomes miR-34a-5p could aggravate the development of urethral fibrosis and stricture by blocking autophagosome-lysosome fusion in urethral fibroblasts and further accelerating fibrogenesis by directly targeting SIRT1, suggesting that M2-Exo miR-34a-5p and SIRT1 could serve as promising therapeutic targets for urethral stricture.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"151-173"},"PeriodicalIF":6.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}