ImmunoTargets and Therapy最新文献

{"title":"Adaptation of Natural Killer Cells to Hypoxia: A Review of the Transcriptional, Translational, and Metabolic Processes.","authors":"Te-Ding Chang, Yu-Jie Chen, Jia-Liu Luo, Cong Zhang, Shun-Yao Chen, Zhi-Qiang Lin, Pei-Dong Zhang, You-Xie Shen, Ting-Xuan Tang, Hui Li, Li-Ming Dong, Zhao-Hui Tang, Deng Chen, Yu-Man Wang","doi":"10.2147/ITT.S492334","DOIUrl":"10.2147/ITT.S492334","url":null,"abstract":"<p><p>As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"99-121"},"PeriodicalIF":6.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484087","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":"Genetic and Plasma Proteomic Approaches to Identify Therapeutic Targets for Graves' Disease and Graves' Ophthalmopathy.","authors":"Chenxin Ke, Yuefeng Yu, Jiang Li, Yuetian Yu, Ying Sun, Yuying Wang, Bin Wang, Yingli Lu, Mengjun Tang, Ningjian Wang, Yi Chen","doi":"10.2147/ITT.S494692","DOIUrl":"10.2147/ITT.S494692","url":null,"abstract":"<p><strong>Background: </strong>The blood proteome is a major source of biomarkers and therapeutic targets. We aimed to identify the causal proteins and potential targets for Graves' disease (GD) and Graves' ophthalmopathy (GO) via systematic genetic analyses.</p><p><strong>Methods: </strong>Genome-wide association studies (GWASs) on the UK Biobank- Pharma Proteomics Project (UKB-PPP) collected 2923 Olink proteins from 54,219 participants. We conducted a proteome-wide Mendelian randomization (MR) study with cis-pQTLs to identify candidate proteins for GD and GO risk. Colocalization analysis and the Heidi test were used to examine whether the identified proteins and diseases shared the same variant. More proteins with potential causal associations were identified in Summary-data-based MR (SMR) analyses using trans-pQTLs. Then, downstream analyses were performed to detect protein interactions, gene function, cell type-specific expression and druggable information.</p><p><strong>Results: </strong>This study genetically predicted levels of 62 plasma proteins were associated with GD risk. Four proteins (CD40, TINAGL1, GMPR and CXCL10) were prioritized with the evidence of sharing the same variants with GD. Specifically, some proteins had potential associations with GD with trans-pQTLs mapping in CD40. The four prioritized protein-coding genes were mainly enriched in the regulation of apoptotic and death processes. In addition, GMPR was associated with both GO and GD in a consistent direction. BTN1A1 and FCRL1 were prioritized as the causal proteins for GO onset and were not associated with GD.</p><p><strong>Conclusion: </strong>By synthesizing proteomic and genetic data, we identified several protein biomarkers for GD, with one linked to both GD and GO and two other protein biomarkers specific to GO onset, which provides valuable insights into the etiology and potential therapeutic targets for the two diseases.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"87-98"},"PeriodicalIF":6.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400298","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":"Identification of EARS2 as a Potential Biomarker with Diagnostic, Prognostic, and Therapeutic Implications in Colorectal Cancer.","authors":"Ling Wang, Xuemei Deng, Jiaxi Tang, Yi Gong, Shaojin Bu, Zuli Li, Bin Liao, Yao Ding, Tingting Dai, Yong Liao, Yongsheng Li","doi":"10.2147/ITT.S499680","DOIUrl":"10.2147/ITT.S499680","url":null,"abstract":"<p><strong>Purpose: </strong>Colorectal cancer (CRC) is a prevalent malignancy, and lactate metabolism significantly influences tumorigenesis and progression. This study identifies key genes associated with lactic acid metabolism and explore their impact on CRC.</p><p><strong>Patients and methods: </strong>This study utilized data from The Cancer Genome Atlas, Gene Expression Omnibus, other public databases, and our institutional resources. Machine learning identified key lactate metabolism-related genes. Receiver Operating Characteristic analysis, Kaplan-Meier analysis, and the construction of a nomogram model were conducted to assess the diagnostic and prognostic significance of the key lactate metabolism-related gene EARS2. EARS2 expression in colorectal tissue was validated using both publicly available external data and samples from our institution. To investigate the mechanisms underlying EARS2 in CRC, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis, and Protein-Protein Interaction analyses were performed, alongside the construction of miRNA-mRNA interaction networks. Additionally, the relationships between EARS2 and immune cell infiltration, as well as responses to drug therapy, were examined. Following the knockdown of EARS2, we assessed cell proliferation, migration capabilities, and apoptosis. Statistical analyses were conducted using R and GraphPad Prism software.</p><p><strong>Results: </strong>ERAS2 was overexpressed in CRC tissues compared to normal and adenoma tissues, with higher expression levels correlating with aberrant lactate metabolism and poorer patient prognosis. EARS2 was involved in pathways such as neuroactive ligand-receptor interactions, protein digestion, and cholesterol metabolism, and it was associated with immune cell infiltration and responses to drug treatment. Additionally, the knockdown of EARS2 inhibited the proliferation, migration, and invasion of CRC cells while enhancing their apoptosis.</p><p><strong>Conclusion: </strong>Elevated expression of EARS2 is associated with abnormal lactate metabolism, immune cell infiltration, altered therapeutic sensitivity, and poorer survival outcomes in CRC. This correlation suggests that EARS2 may serve as a potential target for the diagnosis, prognosis, and therapeutic intervention in CRC.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"65-85"},"PeriodicalIF":6.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190365","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":"PD(L)1 Inhibitors Plus Lenvatinib Vs Atezolizumab Plus Bevacizumab Combined With HAIC for Unresectable HCC: A Propensity Score Matching Study.","authors":"Zhaoqian He, Hua Chen, Chen Liang, Xiang Tang, Lingmin Jiang, Feihu Xie, Qi Liu, Yun Zheng","doi":"10.2147/ITT.S502350","DOIUrl":"10.2147/ITT.S502350","url":null,"abstract":"<p><strong>Purpose: </strong>To compare the clinical outcomes of different systemic therapies, specifically PD(L)1 inhibitors plus Lenvatinib versus Atezolizumab plus Bevacizumab, when combined with hepatic arterial infusion chemotherapy (HAIC) based on the FOLFOX regimen (oxaliplatin, fluorouracil, and leucovorin) as first line treatment for unresectable hepatocellular carcinoma.</p><p><strong>Patients and methods: </strong>This real-world retrospective study enrolled 294 patients with unresectable HCC. All patients received HAIC in combination with either PD(L)1 inhibitors plus Lenvatinib (PLEN-HAIC) or Atezolizumab plus Bevacizumab (AT-HAIC). Propensity score matching (PSM) was performed to balance patient characteristics. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared.</p><p><strong>Results: </strong>After PSM, 80 and 130 patients received AT-HAIC and PLEN-HAIC, respectively. No significant differences were found in ORR between the AT-HAIC and PLEN-HAIC groups (50.0% vs 40.0% per RECIST, p = 0.202; 60.0% vs 57.7% per mRECIST, p = 0.853). Both groups showed similar disease control rates. Median PFS was 14.3 months for PLEN-HAIC versus 8.8 months for AT-HAIC (p = 0.018). Median OS was significantly better in the PLEN-HAIC group (p = 0.045, both not reached). Subgroup analysis revealed that Lenvatinib showed a better OS compared to Bevacizumab when combined with HAIC and PDL1 inhibitors (p = 0.023).</p><p><strong>Conclusion: </strong>PLEN-HAIC offers significant survival benefits over AT-HAIC in advanced HCC. Given its remarkable efficacy, PLEN-HAIC could be a promising first-line option for unresectable HCC.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"51-63"},"PeriodicalIF":6.2,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068289","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":"Pan-Cancer Analysis of the Prognostic and Immunotherapeutic Value of PDGFB.","authors":"Yuwei Bai, Xiaoyun Wang, Bei Wang","doi":"10.2147/ITT.S486609","DOIUrl":"10.2147/ITT.S486609","url":null,"abstract":"<p><strong>Introduction: </strong>Cancer is a widespread epidemic that affects millions of individuals across the world. Identifying novel cancer targets is crucial to developing more effective cancer treatments. Platelet-derived growth factor-B (PDGFB) plays a critical role in various tumor processes, including angiogenesis and lymphatic metastasis. However, there is a lack of research on the role of PDGFB in these processes.</p><p><strong>Methods: </strong>To address this issue, we conducted a comprehensive analysis utilizing multiple online databases to investigate the expression, prognostic, tumor stemness, and immunological effect of PDGFB. In addition, clinical samples were validated using immunohistochemistry.</p><p><strong>Results: </strong>Our findings revealed that PDGFB was highly expressed in a diverse range of cancer types, and its expression and genetic modifications were significantly associated with clinical outcomes in certain tumors. In general, high expression of PDGFB in tumors is associated with poor prognosis. Surprisingly, PDGFB was found to be highly expressed in renal clear cell carcinoma but was associated with good prognosis. In contrast, PDGFB was low expressed in lung carcinoma, but its expression was found to improve patient survival. These findings demonstrate the complex role of PDGFB in different cancer types. The study also demonstrated that PDGFB was linked to RNA and DNA stemness in 15 and 36 tumor types, respectively, and had a positive association with tumor lymphocyte infiltration. Notably, PDGFB was found to be associated with immune modulators. PDGFB, which is involved in various immune responses, influences the malignant characteristics of various cancer types and controls immune cell infiltration. We confirmed that PDGFB positively correlated with CD8 and PDL1 expression in lower grade glioma.</p><p><strong>Conclusion: </strong>This study concludes that PDGFB may serve as a potential prognostic marker and a potential targetable pathway in cancer immunotherapy. Overall, the study sheds new light on the role of PDGFB in cancer and highlights its potential clinical significance.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"35-49"},"PeriodicalIF":6.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053708","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":"Increased Co-Expression of PD-L1 and CTLA-4 Predicts Poor Overall Survival in Patients with Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation.","authors":"Cunte Chen, Kangjie Qiu, Jie Chen, Shunqing Wang, Yuping Zhang, Caixia Wang, Yangqiu Li","doi":"10.2147/ITT.S500723","DOIUrl":"10.2147/ITT.S500723","url":null,"abstract":"<p><strong>Purpose: </strong>Our previous study has demonstrated that high expression of immune checkpoints (ICs) was significantly associated with adverse clinical outcomes in patients with acute myeloid leukemia (AML). This study aims to investigate the significance of the alteration of IC co-expression for evaluating the prognosis of AML patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).</p><p><strong>Patients and methods: </strong>Quantitative real-time PCR (qRT-PCR) data of bone marrow (BM) samples from 62 de novo AML patients, including 37 patients who received allo-HSCT and 25 patients who received chemotherapy only, were used for prognostic analysis.</p><p><strong>Results: </strong>High expression of PD-1, PD-L1, PD-L2, CTLA-4, and LAG-3 was associated with poor overall survival (OS) in AML patients receiving allo-HSCT, while the expression levels of PD-1, PD-L2, CTLA-4, and LAG-3, other than PD-L1, were not significantly correlated with OS in AML patients receiving chemotherapy. Importantly, PD-L1/CTLA-4 was the best combination model for predicting poor OS in AML patients following allo-HSCT, especially combined with minimal residual disease (MRD).</p><p><strong>Conclusion: </strong>High expression of ICs in BM of AML patients following allo-HSCT was related to poor outcomes, and increasing co-expression of PD-L1 and CTLA-4 might be one of the best immune biomarkers to predict outcomes in patients with AML.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"25-33"},"PeriodicalIF":6.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048041","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":"Targeting B and T Lymphocyte Attenuator Regulates Lupus Disease Development in NZB/W Mice.","authors":"Léa Gherardi, Lucie Aubergeon, Mélanie Sayah, Jean-Daniel Fauny, Hélène Dumortier, Fanny Monneaux","doi":"10.2147/ITT.S490573","DOIUrl":"10.2147/ITT.S490573","url":null,"abstract":"<p><strong>Purpose: </strong>The co-inhibitory receptor B and T Lymphocyte Attenuator (BTLA) negatively regulates B and T cell activation. We have previously shown an altered BTLA expression by regulatory T cells and an impaired capacity of BTLA to inhibit CD4⁺ T cell activation in lupus patients. In this study, we analyzed BTLA expression and function in the NZB/W lupus-mouse model and examined the therapeutic potential of BTLA targeting.</p><p><strong>Methods: </strong>BTLA expression and function were analyzed in young (10-12-week-old) and old-diseased NZB/W mice (>35-week-old with proteinuria) in comparison to age-related BALB/W control mice. 20-22 weeks old NZB/W mice (n=10) were injected i.p with 3 mg/kg, twice a week for ten weeks, with the anti-BTLA antibody 6F7 or its isotype control.</p><p><strong>Results: </strong>In old-diseased NZB/W mice, BTLA expression is slightly modified in B cell subsets whereas CD4⁺ T cells display impaired BTLA functionality. Administration of the 6F7 anti-BTLA antibody into 20-22 week-old NZB/W mice resulted in a delayed onset of proteinuria (p<0.01), limited kidney damages (p<0.05) and an increased survival rate (p<0.01) compared to isotype-treated mice. This beneficial effect was associated with a decrease in circulating B cell and spleen follicular B cell numbers. Regarding its mode of action, we demonstrated that the 6F7 antibody is not a depleting antibody and does not block HVEM binding to BTLA, but instead induces BTLA down modulation and exhibits in vivo agonist activity.</p><p><strong>Conclusion: </strong>Overall, our data confirm the involvement of BTLA in lupus pathogenesis and provide the first evidence that BTLA is a potential therapeutic target for the treatment of lupus.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"7-23"},"PeriodicalIF":6.2,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024958","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":"Daratumumab and Romiplostim Combined Therapy for a Long-Standing Refractory Primary Immune Thrombocytopenia - Case Report.","authors":"Ibrahim Zoubi, Amir Warwar, Shoshan Perek, Meir Preis","doi":"10.2147/ITT.S487895","DOIUrl":"10.2147/ITT.S487895","url":null,"abstract":"<p><p>Multi-refractory immune thrombocytopenia (ITP) is not uncommon and associated with high morbidity and mortality rates. Although the precise mechanism of ITP is not yet fully understood, a therapeutic approach that relies on using a single agent in each treatment line may not be sufficient in this population. We report the case of a 67-year-old female with long-standing multi-refractory ITP treated with a combination of Daratumumab and Romiplostim who achieved a durable response for more than 42 weeks. Owing to the presentation of chronic and refractory disease, we used a dual-agent approach to address early immune destruction and promote megakaryocyte platelet production. Three doses of Daratumumab were administered during the induction phase (weeks 0,1,5) and then at less frequent intervals - every 4-12 weeks for total of 4 doses during the maintenance phase. Romiplostim was administered weekly, with dose modification depending on the platelet count. We hypothesize that when combined with thrombopoietin receptor agonists (TPO-RAs), daratumumab administered at less frequent intervals over an extended period can be safely used, resulting in a prolonged response.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"1-5"},"PeriodicalIF":6.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972404","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":"Anti-GluK2 Encephalitis in an Asian Child: A Case Report and Literature Review.","authors":"Shimeng Chen, Miriam Kessi, Fang He, Fei Yin, Jing Peng, Lifen Yang","doi":"10.2147/ITT.S498345","DOIUrl":"10.2147/ITT.S498345","url":null,"abstract":"<p><strong>Background: </strong>Anti-glutamate kainate receptor subunit 2 (anti-GluK2) antibodies mediated encephalitis is very rare in both children and adults. This study aimed to describe the second report of the anti-GluK2 encephalitis worldwide, the first youngest patient worldwide, and the first case ever in Asia. Besides, this study provides a summary of the clinical manifestations of all previous reported cases.</p><p><strong>Methods: </strong>The patient was attended at the Department of Pediatrics, Xiangya Hospital, Central South University. Anti-GluK2 antibodies were tested in the serum and cerebrospinal fluid (CSF) by the indirect immunofluorescence on cell-based assays. The clinical information of the patient was collected. In addition, a literature search was carried out in the PubMed.</p><p><strong>Results: </strong>Our patient was a male who presented with lethargy, recurrent dizziness and vomiting, headache and cerebellar ataxia at the age of 13 years. Prodromal illnesses included Herpes Zoster infection and Mycoplasma pneumonia. The anti-GluK2 antibodies and elevated IL-6 levels were detected in serum while high oligoclonal bands levels were found in the CSF. The intravenous methylprednisolone, immunoglobulin, antibiotics and other symptomatic treatments helped the patient to recover full. We could only find one previous report in the literature (from Barcelona). The literature review plus our report unveiled eight patients with pure anti-GluK2 antibodies related encephalitis. The median age of onset was 28.50 years and majority were males (75.00%). Most of the cases (87.50%) presented with acute cerebellitis symptoms and signs. Preceding or concurrent infection was observed in two patients, while paraneoplastic tumors were observed in two patients. Patients had non-parenchymal brain lesions; the commonest anomalies were those localized in the cerebellum (62.50%).</p><p><strong>Conclusion: </strong>Our report provides more evidence that anti-GluK2 antibodies may be pathogenic for the autoimmune encephalitis (cerebellitis). Immunotherapy can be used to treat it with good outcome.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"805-811"},"PeriodicalIF":6.2,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883123","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":"Lipopolysaccharide in Bile Promotes the Neutrophil Extracellular Traps-Induced Gallstone Formation by Activating the Gallbladder Immune Barrier.","authors":"Jingjing Yu, Ziang Meng, Xuxu Liu, Yi Zheng, Dongbo Xue, Chenjun Hao, Liyi Wang","doi":"10.2147/ITT.S495095","DOIUrl":"10.2147/ITT.S495095","url":null,"abstract":"<p><strong>Background: </strong>Cholelithiasis areis a common digestive system disorder, with cholesterol gallstones being the most prevalent type. Gallstones lead to many severe complications, posing a significant burden on global healthcare systems. Many studies have shown associations between biliary microbiota, gallbladder immune microenvironment, and gallstone formation. However, the specific immune mechanisms underlying the cholesterol gallstone formation have not been fully elucidated.</p><p><strong>Methods: </strong>In this study, gallbladderand bile samples from 8 asymptomatic patients with cholelithiasis undergoing cholecystectomy and 11 healthy liver transplant donors were collected for tissue transcriptome sequencing and differential analysis. Male C57BL/6J mice were fed a normal or lithogenic diet for 6 weeks. Starting from the third week, lipopolysaccharide (LPS) or specific regulators were injected intraperitoneally once a week for a total of 3 times. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence were employed for quantitative, qualitative or localization analysis of LPS, neutrophil extracellular traps (NETs), inflammatory factors, proteins, and mRNAs using samples collected from mice.</p><p><strong>Results: </strong>In patients with cholelithiasis, the gallbladder mechanical barrier is impaired, resulting in an immune-activated state. LPS induces damage to the gallbladder mucosal mechanical barrier through the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, it stimulates the continuous production of NETs through the TLR4/Phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, aggravating the formation of gallstones.</p><p><strong>Conclusion: </strong>With the biliary dysbiosis, excessive LPS can invade the submucosa of the gallbladder, leading to chronic inflammation that recruits neutrophils to form NETs, which are ultimately expelled into bile, thereby promoting the formation of gallstones.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"789-803"},"PeriodicalIF":6.2,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877878","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}