ImmunoTargets and Therapy最新文献

{"title":"Cytokine Couture: Designer IL2 Molecules for the Treatment of Disease.","authors":"Amy Dashwood, Arman Ali Ghodsinia, James Dooley, Adrian Liston","doi":"10.2147/ITT.S500229","DOIUrl":"https://doi.org/10.2147/ITT.S500229","url":null,"abstract":"<p><p>Interleukin 2 (IL2) is a dual-acting cytokine, playing important roles in both immune activation and regulation. The role IL2 plays as a potent activator of CD8 T cells saw IL2 become one of the earliest immunotherapies, used for the treatment of cancer. In more recent years refined understanding of IL2, and the potent capacity it has for Treg stimulation, has seen low-dose IL2 therapy trialled for the treatment of auto-immune and inflammatory conditions. However, despite clinical successes, IL2 therapy is not without its caveats. The complicated receptor biology of IL2 gives rise to a narrow therapeutic window, made problematic by its short half-life. Armed with a better understanding of the structure of IL2 in complex with its receptors, many attempts have been made to create designer IL2 molecules which overcome these problems. A wide range of approaches have been used, resulting in >100 designer IL2 molecules. These include antibody complexes, fusion proteins, mutant IL2 molecules and PEGylation, each uniquely modifying the biological activity in an effort to enhance its therapeutic potential. Collectively, designer IL2 molecules form a blueprint outlining modification pathways available to other immunotherapeutics, paving the way for the next generation of immunotherapy.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"403-431"},"PeriodicalIF":6.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812648","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":"Comprehensive Analyses of Single-Cell and Bulk RNA Sequencing Data From M2 Macrophages to Elucidate the Immune Prognostic Signature in Patients with Gastric Cancer Peritoneal Metastasis.","authors":"Qiao Tang, Liang Tang, Xiaofeng Wang, Yongxin Zhang, Wenwei Liu, Ting Yang, Yuxin Wu, Yuanchen Ma, Tianxiang Lei, Wu Song","doi":"10.2147/ITT.S506143","DOIUrl":"https://doi.org/10.2147/ITT.S506143","url":null,"abstract":"<p><strong>Purpose: </strong>The peritoneum is a common site of metastasis in gastric cancer (GC), associated with poor prognosis and significant morbidity. The proclivity of GCs to metastasize to the peritoneum has been hypothesized to occur due the latter's immunosuppressive microenvironment, such as stromal infiltration and M2 macrophage enrichment, which are associated with increased risk of PM. As far as we know, a model that can effectively predict the prognosis of patients with GCPM is still lacking. Consequently, we constructed a prognostic risk model based on M2 macrophages associated with gastric cancer peritoneal metastasis, aiming to enhance predictive precision and guide tailored therapeutic interventions.</p><p><strong>Methods: </strong>M2 macrophage-associated genes were identified in combination with marker genes from single-cell RNA sequencing (scRNA-seq) and modular genes from weighted gene coexpression network analysis (WGCNA). A prognostic model was constructed via LASSO analysis and validated in internal and external cohorts. We further compared the immune microenvironment, immune checkpoints, and chemotherapeutic drug sensitivity between patient groups stratified by risk to clarify the immune landscape in the GCPM.</p><p><strong>Results: </strong>Our study identified 38 M2 macrophage-related genes via single-cell and bulk RNA sequencing. We developed a prognostic model based on the expression levels of 4 signature genes: DAB2, SPARC, PLTP, and FOLR2. The feasibility of the model was validated with internal and external validation sets (TCGA, GSE62254 and IMvigor210). The model also supported the prediction results of prognosis on the basis of the immunohistochemical results. Notably, patients with higher risk scores had a lower proportion of MSI-H and TMB, a higher prevalence of stages III-IV, and a lower likelihood of responding favorably to immunotherapy.</p><p><strong>Conclusion: </strong>Our prognostic risk model could effectively predict the prognosis and response to chemo-immune therapy in patients with GCPM. The risk score is a promising independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"383-402"},"PeriodicalIF":6.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812645","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":"Interplay Between Insulin Resistance and Immune Dysregulation in Type 2 Diabetes Mellitus: Implications for Therapeutic Interventions.","authors":"Afiat Berbudi, Shafia Khairani, Adi Imam Tjahjadi","doi":"10.2147/ITT.S499605","DOIUrl":"10.2147/ITT.S499605","url":null,"abstract":"<p><p>Type 2 Diabetes Mellitus (T2DM) is a rapidly growing global health issue characterized by insulin resistance and chronic inflammation. Beyond regulating glucose homeostasis, insulin plays a pivotal role in modulating immune cell function, linking metabolic dysregulation with immune responses. This review examines the intricate relationship between insulin resistance and immune dysfunction in T2DM, focusing on how impaired insulin signaling pathways, particularly PI3K/Akt and MAPK, contribute to immune cell activation, proliferation, and chronic inflammation. Insulin resistance impacts immune cells such as T cells, B cells, macrophages, and neutrophils, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. Elevated pro-inflammatory cytokines (eg, TNF-α, IL-6) and adipokines (eg, leptin, resistin) exacerbate insulin resistance, promoting a vicious cycle of metabolic and immune dysregulation. This interplay contributes to the chronic low-grade inflammation that underlies T2DM pathogenesis, further impairing insulin signaling and glucose metabolism. Restoration of insulin sensitivity is, therefore, a critical step toward correcting immune imbalance in insulin-resistant states like T2DM. Therapeutic approaches that reduce inflammation could also support improvements in insulin sensitivity, addressing both metabolic and immune disturbances simultaneously. The review also explores therapeutic strategies, including insulin therapy, targeting insulin signaling pathways, and lifestyle interventions. Insulin therapy can reduce pro-inflammatory cytokine production and enhance anti-inflammatory responses, although challenges such as potential immune suppression and hyperinsulinemia remain. Targeting key signaling pathways and transcription factors offers promising avenues for modulating immune responses, while lifestyle interventions, such as dietary modifications, physical activity, and weight management, can improve insulin sensitivity and reduce inflammation. By understanding the dual role of insulin in regulating both metabolic and immune functions, this review underscores the importance of addressing immune dysfunction as part of comprehensive T2DM management. Targeting the interconnected pathways of insulin signaling and immune regulation could lead to more effective therapeutic approaches, ultimately improving patient outcomes and reducing disease complications.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"359-382"},"PeriodicalIF":6.2,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804419","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":"Recent Advances in Immune Checkpoint Inhibitors for Triple-Negative Breast Cancer.","authors":"Chiara Corti, Beyza Koca, Tasnim Rahman, Elizabeth A Mittendorf, Sara M Tolaney","doi":"10.2147/ITT.S495751","DOIUrl":"10.2147/ITT.S495751","url":null,"abstract":"<p><p>While immunotherapy has transformed treatment across various cancers, its impact on breast cancer is relatively limited. Recent advances have established immunotherapy as an effective approach for triple-negative breast cancer (TNBC), an aggressive subtype with limited therapeutic targets and poor prognosis. Specifically, pembrolizumab, an immune checkpoint inhibitor (ICI), is now approved for both first-line metastatic and early-stage TNBC. In metastatic TNBC, combining ICIs with chemotherapy, particularly pembrolizumab, has demonstrated survival benefits in patients with PD-L1-positive disease. However, extending these benefits to broader populations has proven challenging, highlighting the need for better patient selection and novel strategies. Emerging approaches include combining ICIs with antibody-drug conjugates, PARP inhibitors, dual ICIs, and bispecific antibodies targeting angiogenesis and immune checkpoints. These strategies aim to overcome resistance and expand immunotherapy's efficacy beyond the PD-1/PD-L1 pathway. In early-stage disease, pembrolizumab combined with chemotherapy in the neoadjuvant setting has significantly improved pathologic complete response, event-free survival, and overall survival, establishing a new standard of care. Ongoing research aims to determine the optimal timing for ICI administration, explore less toxic chemotherapy backbones, utilize biomarkers for personalized treatment, and assess whether adding complementary treatments, such as radiation therapy for high-risk cases, can improve outcomes. This review examines the successes and setbacks of ICI use in TNBC, offering a comprehensive overview of current practices and future directions. It emphasizes optimizing ICI timing, leveraging biomarkers, and integrating novel agents to refine treatment approaches for both metastatic and early-stage TNBC. As immunotherapy continues to evolve, future research must address the unmet needs of this challenging breast cancer subtype, offering hope for improved outcomes.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"339-357"},"PeriodicalIF":6.2,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804422","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":"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}