Frontiers in ImmunologyPub Date : 2025-03-24eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1554341
Lija Satheesan, Ajay Kumar Dang, Rani Alex
{"title":"Cytokine interactions and chemokine dysregulations in mastitis immunopathogenesis: insights from transcriptomic profiling of milk somatic cells in tropical Sahiwal (<i>Bos indicus</i>) cows.","authors":"Lija Satheesan, Ajay Kumar Dang, Rani Alex","doi":"10.3389/fimmu.2025.1554341","DOIUrl":"10.3389/fimmu.2025.1554341","url":null,"abstract":"<p><strong>Introduction: </strong>Bovine mastitis causes a significant loss to the dairy industry by affecting the quantity and quality of milk. Addressing this challenge, the present study will leverage advanced omics techniques for early mastitis detection in early lactating Sahiwal cows (<i>Bos indicus</i>). This was the first differential transcriptomic study investigating the alterations in gene expression in milk somatic cells during the progression of naturally occurring mastitis in indigenous Sahiwal cows.</p><p><strong>Methods: </strong>Cows were grouped into healthy (H), subclinical mastitis (SCM) and clinical mastitis (CM) groups by thoroughly screening them using the California Mastitis Test (CMT) and milk somatic cell counts (SCC). This was followed by detailed milk composition analysis, differential leukocyte counts (DLC), and microbiological culture.</p><p><strong>Results: </strong>The differential gene expression of milk SCs through transcriptome profiling identified 83 and 76, up-regulated and 157 and 192 down-regulated genes in CM vs H and SCM vs H groups (log2 fold change ≥1 and ≤-1, p < 0.05) respectively. Pathway analysis revealed that upregulated genes were enriched in pathways such as phagosome activity, IL-17 signalling, Th1 and Th2 cell differentiation, while downregulated genes were linked to RIG-I-like receptor signalling, NK cell cytotoxicity, and Toll-like receptor signalling and Cytokine-cytokine receptor interactions. Notably, the study underscores the roles of chemokines CCL8, CCL2, and CXCL10 in immune cell recruitment during mastitis, where their downregulation suggests impaired mammary immune defense that governs Chemokine signalling pathways. Further, the comparative analysis with the previously available milk SCs proteome data identified the downregulation of chemokines signalling pathways during mastitis.</p><p><strong>Discussion: </strong>Overall, this research enhances our understanding of mastitis pathogenesis and emphasizes that these targeted chemokines may boost mammary resilience through immunomodulation, genetic selection and genome editing or by utilising adjuvants in vaccine development that restore chemokine signalling offers a potential strategy to improve mastitis resistance in dairy cattle.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1554341"},"PeriodicalIF":5.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting tumor-associated macrophages in colon cancer: mechanisms and therapeutic strategies.","authors":"Jianqin Xiang, Jian Wang, Huihui Xiao, Chengchen Huang, Chunrong Wu, Lin Zhang, Chenyuan Qian, Debing Xiang","doi":"10.3389/fimmu.2025.1573917","DOIUrl":"10.3389/fimmu.2025.1573917","url":null,"abstract":"<p><p>Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1573917"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Analysis of shared pathogenic mechanisms and drug targets in myocardial infarction and gastric cancer based on transcriptomics and machine learning.","authors":"Junyang Ma, Shufu Hou, Xinxin Gu, Peng Guo, Jiankang Zhu","doi":"10.3389/fimmu.2025.1533959","DOIUrl":"10.3389/fimmu.2025.1533959","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have suggested a potential association between gastric cancer (GC) and myocardial infarction (MI), with shared pathogenic factors. This study aimed to identify these common factors and potential pharmacologic targets.</p><p><strong>Methods: </strong>Data from the IEU Open GWAS project were used. Two-sample Mendelian randomization (MR) analysis was used to explore the causal link between MI and GC. Transcriptome analysis identified common differentially expressed genes, followed by enrichment analysis. Drug target MR analysis and eQTLs validated these associations with GC, and the Steiger direction test confirmed their direction. The random forest and Lasso algorithms were used to identify genes with diagnostic value, leading to nomogram construction. The performance of the model was evaluated via ROC, calibration, and decision curves. Correlations between diagnostic genes and immune cell infiltration were analyzed.</p><p><strong>Results: </strong>MI was linked to increased GC risk (<i>OR</i>=1.112, <i>P</i>=0.04). Seventy-four genes, which are related mainly to ubiquitin-dependent proteasome pathways, were commonly differentially expressed between MI and GC. Nine genes were consistently associated with GC, and eight had diagnostic value. The nomogram built on these eight genes had strong predictive performance (<i>AUC</i>=0.950, validation set <i>AUC</i>=0.957). Immune cell infiltration analysis revealed significant correlations between several genes and immune cells, such as T cells, macrophages, neutrophils, B cells, and dendritic cells.</p><p><strong>Conclusion: </strong>MI is associated with an increased risk of developing GC, and both share common pathogenic factors. The nomogram constructed based on 8 genes with diagnostic value had good predictive performance.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1533959"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-03-21eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1436888
Wenqian Guo, Er Hong, Han Ma, Ji Wang, Qi Wang
{"title":"Effect of the gut microbiome, skin microbiome, plasma metabolome, white blood cells subtype, immune cells, inflammatory proteins, and inflammatory cytokines on asthma: a two-sample Mendelian randomized study and mediation analysis.","authors":"Wenqian Guo, Er Hong, Han Ma, Ji Wang, Qi Wang","doi":"10.3389/fimmu.2025.1436888","DOIUrl":"10.3389/fimmu.2025.1436888","url":null,"abstract":"<p><strong>Background: </strong>Asthma is a chronic inflammatory disorder arising from incompletely understood heterogenic gene-environment interactions. This study aims to investigate causal relationships among gut microbiota, skin microbiota, plasma metabolomics, white blood cells subtype, immune cells, inflammatory proteins, inflammatory cytokines, and asthma.</p><p><strong>Methods: </strong>First, two-sample Mendelian randomization analysis was used to identify causal relationships. The summary statistics of 412 gut microbiota traits (N = 7 738), 150 skin microbiota traits (N = 579), 1 400 plasma metabolite traits (N = 8 299), white blood cells subtype counts (N = 746 667), 731 immune cell traits (N = 3 669), 91 circulating inflammatory proteins (N = 14 744), 41 inflammatory cytokine traits (N = 8 293), and asthma traits (N = 244 562) were obtained from publicly available genome-wide association studies. Inverse-variance weighted regression was used as the primary Mendelian randomization method. A series of sensitivity analyses was performed to test the robustness of causal estimates. Subsequently, mediation analysis was performed to identify the pathway from gut or skin microbiota to asthma mediated by plasma metabolites, immune cells, and inflammatory proteins.</p><p><strong>Results: </strong>Mendelian randomization revealed the causal effects of 31 gut bacterial features (abundances of 19 bacterial pathways and 12 microbiota), 10 skin bacterial features, 108 plasma metabolites (81 metabolites and 27 ratios), 81 immune cells, five circulating inflammatory proteins, and three inflammatory cytokines and asthma. Moreover, the mediation analysis results supported the mediating effects of one plasma metabolite, five immunophenotypes, and one inflammatory protein on the gut or skin microbiota in asthma pathogenesis.</p><p><strong>Conclusion: </strong>The findings of this study support a causal relationship among gut microbiota, skin microbiota, plasma metabolites, immune cells, inflammatory proteins, inflammatory cytokines, and asthma. Mediating pathways through which the above factors may affect asthma were proposed. The biomarkers and mediation pathways identified in this work provide new insights into the mechanism of asthma and contribute to its prevention and treatment.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1436888"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exploration of SUSD3 in pan-cancer: studying its role, predictive analysis, and biological significance in various malignant tumors in humans.","authors":"Fei Zhong, Shining Mao, Shuangfu Peng, Jiaqi Li, YanTeng Xie, Ziqian Xia, Chao Chen, Aijun Sun, Shasha Zhang, Shiyan Wang","doi":"10.3389/fimmu.2025.1521965","DOIUrl":"10.3389/fimmu.2025.1521965","url":null,"abstract":"<p><strong>Background: </strong>The SUSD3 protein, marked by the Sushi domain, plays a key role in cancer progression, with its expression linked to tumor advancement and patient prognosis. Altered SUSD3 levels could serve as a predictive biomarker for cancer progression. Recognized as a novel susceptibility marker, SUSD3 presents a promising target for antibody-based therapies, offering a potential approach for the prevention, diagnosis, and treatment of breast cancer.</p><p><strong>Methods: </strong>Using the HPA and GeneMANIA platforms, the distribution of SUSD3 protein across tissues was analyzed, while expression levels in tumor and healthy tissues were compared using The Cancer Genome Atlas data. The TISCH and STOmics DB databases facilitated the mapping of SUSD3 expression in different cell types and its spatial relationship with cancer markers. Univariate Cox regression assessed the prognostic significance of SUSD3 expression in various cancers. Genomic alterations of SUSD3 were explored through the cBioPortal database. The potential of SUSD3 as a predictor of immunotherapy response was investigated using TIMER2.0, and GSEA/GSVA identified related biological pathways. Drugs targeting SUSD3 were identified through CellMiner, CTRP, and GDSC databases, complemented by molecular docking studies. <i>In vitro</i> experiments demonstrated that SUSD3 knockdown in breast cancer cell lines significantly reduced proliferation and migration.</p><p><strong>Results: </strong>SUSD3 expression variations in pan-cancer cohorts are closely linked to the prognosis of various malignancies. In the tumor microenvironment (TME), SUSD3 is predominantly expressed in monocytes/macrophages and CD4+ T cells. Research indicates a strong correlation between SUSD3 expression and key cancer immunotherapy biomarkers, immune cell infiltration, and immunomodulatory factors. To explore its immune regulatory role, StromalScore, ImmuneScore, ESTIMATE, and Immune Infiltration metrics were employed. Molecular docking studies revealed that selumetinib inhibits tumor cell proliferation. Finally, SUSD3 knockdown reduced cancer cell proliferation and migration.</p><p><strong>Conclusion: </strong>These findings provide valuable insights and establish a foundation for further exploration of SUSD3's role in pan-carcinomas. Additionally, they offer novel perspectives and potential targets for the development of innovative therapeutic strategies in cancer treatment.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1521965"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-03-21eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1561174
Karolina Rassek, Jan Misiak, Tomasz Ołdak, Natalia Rozwadowska, Grzegorz Basak, Tomasz Kolanowski
{"title":"New player in CAR-T manufacture field: comparison of umbilical cord to peripheral blood strategies.","authors":"Karolina Rassek, Jan Misiak, Tomasz Ołdak, Natalia Rozwadowska, Grzegorz Basak, Tomasz Kolanowski","doi":"10.3389/fimmu.2025.1561174","DOIUrl":"10.3389/fimmu.2025.1561174","url":null,"abstract":"<p><p>One of the most successful treatments in hematologic cancer is chimeric antigen receptor (CAR)-T cell-based immunotherapy. However, CAR-T therapy is not without challenges like the costly manufacturing process required to personalize each treatment for individual patients or graft-versus-host disease. Umbilical cord blood (UCB) has been most commonly used for hematopoietic cell transplant as it offers several advantages, including its rich source of hematopoietic stem cells, lower risk of graft-versus-host disease, and easier matching for recipients due to less stringent HLA requirements compared to bone marrow or peripheral blood stem cells. In this review, we have discussed the advantages and disadvantages of different CAR-T cell manufacturing strategies with the use of allogeneic and autologous peripheral blood cells. We compare them to the UCB approach and discuss ongoing pre-clinical and clinical trials in the field. Finally, we propose a cord blood bank as a readily available source of CAR-T cells.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1561174"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-03-21eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1493329
Breanna DiAndreth, Pavlo A Nesterenko, Aaron G Winters, Aaron D Flynn, Claudia A Jette, Vasantika Suryawanshi, Sanam Shafaattalab, Sara Martire, Mark Daris, Elizabeth Moore, Ryan Elshimali, Tanveer Gill, Timothy P Riley, Sara Miller, Chawita Netirojjanakul, Agnes E Hamburger, Alexander Kamb
{"title":"Multi-targeted, NOT gated CAR-T cells as a strategy to protect normal lineages for blood cancer therapy.","authors":"Breanna DiAndreth, Pavlo A Nesterenko, Aaron G Winters, Aaron D Flynn, Claudia A Jette, Vasantika Suryawanshi, Sanam Shafaattalab, Sara Martire, Mark Daris, Elizabeth Moore, Ryan Elshimali, Tanveer Gill, Timothy P Riley, Sara Miller, Chawita Netirojjanakul, Agnes E Hamburger, Alexander Kamb","doi":"10.3389/fimmu.2025.1493329","DOIUrl":"10.3389/fimmu.2025.1493329","url":null,"abstract":"<p><strong>Introduction: </strong>Despite advances in treatment of blood cancers, several-including acute myeloid leukemia (AML)-continue to be recalcitrant. Cell therapies based on chimeric antigen receptors (CARs) have emerged as promising approaches for blood cancers. However, current CAR-T treatments suffer from on-target, off-tumor toxicity, because most familiar blood cancer targets are also expressed in normal lineages. In addition, they face the common problem of relapse due to target-antigen loss. Cell therapeutics engineered to integrate more than one signal, often called logic-gated cells, can in principle achieve greater selectivity for tumors.</p><p><strong>Methods: </strong>We applied such a technology, a NOT gated system called Tmod™ that is being developed to treat solid-tumor patients, to the problem of therapeutic selectivity for blood cancer cells.</p><p><strong>Results: </strong>Here we show that Tmod cells can be designed to target 2-4 antigens to provide different practical and conceptual options for a blood cancer therapy: (i) mono- and bispecific activating receptors that target CD33, a well-known AML antigen expressed on the majority of AML tumors (as well as healthy myeloid cells) and CD43 (SPN), an antigen expressed on many hematopoietic cancers (and normal blood lineages); and (ii) mono- and bispecific inhibitory receptors that target CD16b (FCGR3B) and CLEC9A, antigens expressed on key normal blood cells but not on most blood cancers.</p><p><strong>Discussion: </strong>These results further demonstrate the robust modularity of the Tmod system and generalize the Tmod approach beyond solid tumors.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1493329"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Role of long non-coding RNAs in the regulation of ferroptosis in tumors.","authors":"Ying Ju, Yuanhao Lv, Xu Liu, Jing Lu, Yashen Shi, Huimin Guo, Siguang Xu, Jiaqi Tian, Jun Yang, Jiateng Zhong","doi":"10.3389/fimmu.2025.1568567","DOIUrl":"10.3389/fimmu.2025.1568567","url":null,"abstract":"<p><p>Normal cells begin to grow indefinitely and immortalize to form tumor cells after an external stimulus resulting in a genetic mutation. Effective killing of tumor cells is the basis of various cancer therapies. Ferroptosis is a class of cell death types dependent on iron and cellular lipid peroxidation. Tumors themselves are iron-dependent, and conventional radiotherapy also sensitizes cancer cells to ferroptosis. Increasing the sensitivity of tumor cells to ferroptosis may be a potential therapeutic strategy to overcome the resistance mechanisms of conventional cancer therapy. Long noncoding RNAs (LncRNAs) are a class of transcripts more than 200 nucleotides in length that regulate gene expression at multiple levels and are involved in biological processes such as cell differentiation, cell cycle arrest, and maintenance of tumor stemness. Recent studies have found that lncRNAs regulate ferroptosis of tumor cells through multiple mechanisms and may influence or ameliorate tumor resistance to chemotherapeutic agents. With the continuous maturation of nanomaterials technology, it may provide new means for cancer treatment by regulating the levels of ferroptosis-related lncRNAs inside tumors as well as increasing the levels of Fe<sup>2+</sup> and ROS inside tumors. In this paper, we systematically introduce the regulatory mechanism of lncRNAs in ferroptosis, the role of ferroptosis in tumor immunotherapy and the application of lncRNAs combined with ferroptosis in nanomaterials, which provides new perspectives for tumor therapy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1568567"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Immunosuppression of spleen in mice treated with erythropoietin: transcriptomic and immunological analysis.","authors":"Xinyi Lyu, Jiahao Shi, Qi Liu, Mingjun Jiang, Xilian Liu, Yulan Li, Shuqin Ding, Xianpeng Dai","doi":"10.3389/fimmu.2025.1560589","DOIUrl":"10.3389/fimmu.2025.1560589","url":null,"abstract":"<p><strong>Background and aim: </strong>Long term high-dose erythropoietin (EPO) had been reported inducing the formation of abdominal aortic aneurysm (AAA) in mice. When using this model, we found that EPO treated mice showed significant splenomegaly. This is an interesting phenomenon, and its mechanism has not been reported. Therefore, this study aims to explore its mechanism.</p><p><strong>Methods: </strong>C57BL/6 mice were given intraperitoneal injection of recombinant human EPO at 10000 IU/kg/day, and the control mice were treated with normal saline (vehicle). After 3 weeks, the spleens were harvested. Pathological changes in histology were observed using Hematoxylin and Eosin (H&E) staining. The differential expression genes (DEGs) were identified using RNA sequencing (RNA-Seq), verified with the real-time quantitative polymerase chain reaction (RT-qPCR). The functional-enrichment analysis including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome enrichment analysis were performed to reveal the functional characteristics and related biological pathways of DEGs. Immunohistofluorescence (IHF) and flow cytometry (FCM) were used to detect immune cell subsets and proliferation markers.</p><p><strong>Results: </strong>EPO treatment resulted in splenomegaly, spleen microstructure disorder, splenic corpuscular atrophy, indistinct germinal center, and unclear boundary between white and red pulp structures. RNA-Seq showed that EPO treatment suppressed gene expression associated with immune responses, while promoted cell cycle and DNA replication. IHF and FCM validated that, at the cellular level, T, B, M1 cells were significantly reduced, and M2 cells were significantly decreased after EPO treatment. The proliferation analysis showed that the portion of EDU<sup>+</sup> or Ki-67<sup>+</sup>cells consisted of granulocytes and macrophages, and after EPO treatment, only macrophages showed a significant increase in their number and proportion, while granulocytes did not show a significant response to EPO stimulation.</p><p><strong>Conclusion: </strong>Long term high-dose EPO treatment may lead to splenomegaly and immunosuppression of the local immune microenvironment in mice. The mechanism may be related to the increased anti-inflammatory and immunomodulatory functions caused by M2 cells. The study provides, for the first time, the transcriptomic characteristics and immunological of the spleens of EPO treated mice, providing a new perspective for the study of the effects of EPO on mice.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1560589"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-03-21eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1525166
Ewelina Wawryk-Gawda, Michał K Zarobkiewicz, Marta Wolanin-Stachyra, Violetta Opoka-Winiarska
{"title":"Inflammatory markers activation associated with vapor or smoke exposure in Wistar rats.","authors":"Ewelina Wawryk-Gawda, Michał K Zarobkiewicz, Marta Wolanin-Stachyra, Violetta Opoka-Winiarska","doi":"10.3389/fimmu.2025.1525166","DOIUrl":"10.3389/fimmu.2025.1525166","url":null,"abstract":"<p><p>Electronic cigarettes (e-cigarettes) were introduced two decades ago as a safer alternative to traditional cigarettes, aiming to assist in smoking cessation. However, the global use of e-cigarettes has surged, with the highest prevalence among adolescents and young adults. Despite their popularity, the safety of e-cigarettes remains controversial, with emerging evidence linking their use to various health risks, including cardiovascular issues, respiratory diseases, and a condition known as e-cigarette or vaping use-associated lung injury (EVALI). In this study, we investigated the inflammatory response in rats exposed to e-cigarette vapor compared to traditional cigarette smoke. We measured the serum concentrations of inflammatory markers such as IL-10, IFN-γ, IL-5, IL-2, TNF-α, GM-CS, IL-4, IL-9, IL-17F, IL-17A, IL-13, and IL-22 in the serum of rats subjected to 6 weeks of exposure. We assessed the activation of <i>Nf-κb</i>, <i>Stat3</i>, and <i>Socs3</i> genes and the expression of CXCL2 in lung tissues. Our results revealed a significant increase in proinflammatory cytokines, particularly in the vapor-exposed group. We did not observe any statistically significant difference in the activation levels of <i>Nf-κb</i>, <i>Stat3</i>, and <i>Socs3</i> between the groups of rats, but we noted the predictable correlations between IL-22 and IL-2, IL-6 and IL-2, IL-9 and IL-2, IL-6 and IL-9, IL-22 and IL-17F, IL-6 and IL-17F, IL-6 and IL-5, IL-2 and IL-17F, IL-13 and IL-4, and IL-5 and IL-4. In IHC staining, we observed a higher number of CLCX2-positive cells in the lung tissues in groups 2 and 3 compared to the control group. Interestingly, after a 2-week cessation period, inflammatory markers largely normalized, except for IL-17F and IL-13, which remained elevated in the cigarette smoke-exposed group. Our results suggest that while e-cigarette use may trigger a potent inflammatory response, the effects may be reversible upon cessation, albeit with some cytokines persisting longer in traditional cigarette users. Although the immune response has normalized, the increased tendency toward lung fibrosis may lead to permanent structural changes. Further research is needed to fully elucidate the clinical implications of these findings and assist in implementing legal regulations regarding the availability of e-cigarettes in the market.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1525166"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}