Pub Date : 2025-05-30DOI: 10.1016/j.cellimm.2025.104985
Luis Eduardo Alves Damasceno , Gabriel Alberto de Carvalho Barbosa , Tim Sparwasser , Thiago Mattar Cunha , Fernando Queiroz Cunha , José Carlos Alves-Filho
Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance to self-antigens and suppression of excessive immune responses. They employ a distinct metabolic profile from other CD4 T cell subsets to support their differentiation and suppressive function, which is characterized by enhanced mitochondrial metabolism. Although PGC1α is considered a master regulator of mitochondrial biogenesis and function, its role in Treg cell differentiation remains unclear. Herein, we demonstrated that PGC1α is highly expressed in Treg cells compared to other CD4 T cell populations. Using a pharmacological approach, we found that its transcriptional activation in iTreg cells enhanced mitochondrial fitness, characterized by increased expression of mitochondrial genes, mitochondrial mass, and metabolic activity. Moreover, PGC1α activation enhanced both mouse and human iTreg cell differentiation, while its inhibition reduced this process. Therefore, our findings shed light on the potential role of PGC1α as a pharmacological target when manipulating Treg cells as a therapeutic strategy.
{"title":"PGC1α-mediated mitochondrial fitness promotes Treg cell differentiation","authors":"Luis Eduardo Alves Damasceno , Gabriel Alberto de Carvalho Barbosa , Tim Sparwasser , Thiago Mattar Cunha , Fernando Queiroz Cunha , José Carlos Alves-Filho","doi":"10.1016/j.cellimm.2025.104985","DOIUrl":"10.1016/j.cellimm.2025.104985","url":null,"abstract":"<div><div>Regulatory T (T<sub>reg</sub>) cells play a critical role in the maintenance of immune tolerance to self-antigens and suppression of excessive immune responses. They employ a distinct metabolic profile from other CD4 T cell subsets to support their differentiation and suppressive function, which is characterized by enhanced mitochondrial metabolism. Although PGC1α is considered a master regulator of mitochondrial biogenesis and function, its role in T<sub>reg</sub> cell differentiation remains unclear. Herein, we demonstrated that PGC1α is highly expressed in T<sub>reg</sub> cells compared to other CD4 T cell populations. Using a pharmacological approach, we found that its transcriptional activation in iT<sub>reg</sub> cells enhanced mitochondrial fitness, characterized by increased expression of mitochondrial genes, mitochondrial mass, and metabolic activity. Moreover, PGC1α activation enhanced both mouse and human iT<sub>reg</sub> cell differentiation, while its inhibition reduced this process. Therefore, our findings shed light on the potential role of PGC1α as a pharmacological target when manipulating T<sub>reg</sub> cells as a therapeutic strategy.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"414 ","pages":"Article 104985"},"PeriodicalIF":3.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-27DOI: 10.1016/j.cellimm.2025.104976
Xiaohui Li , Xiujuan Song , Fei Yi , Huiqing Hou
Background
Neuroinflammation, a defining feature of numerous neurological disorders, arises predominantly from activating immune cells such as microglia, which play a critical role in maintaining homeostasis within the central nervous system. Microglial activation and polarization exhibit a dual nature, mediating both neuroprotective and neurotoxic effects. Fibrinogen, as a potent pro-inflammatory mediator, interacts with microglia and is implicated in the progression of various neurological conditions. This study investigates the effects of fibrinogen and the exogenous STAT3 inhibitor cryptotanshinone on primary microglial function.
Methods
Primary microglial cells were isolated from neonatal C57BL/6 mice and subsequently treated with fibrinogen and the STAT3 inhibitor cryptotanshinone. Inflammatory marker expression was quantified by quantitative polymerase chain reaction, while protein levels of JAK2 and STAT3 were determined using immunofluorescence and Western blot analysis.
Results
Fibrinogen exposure upregulated STAT3 and JAK2 phosphorylation in primary microglial cells. Cryptotanshinone treatment effectively attenuated STAT3 phosphorylation while concurrently downregulating JAK2 activation. Furthermore, fibrinogen significantly enhanced the release of pro-inflammatory cytokines, such as IL-6 and IL-1β, while the transcription levels of TGF-β remained unchanged.
Conclusions
This study demonstrates that fibrinogen stimulates the production of pro-inflammatory cytokines in primary microglial cells by activating the JAK2/STAT3 signaling pathway. These findings provide mechanistic insights into fibrinogen-induced neuroinflammation and suggest potential therapeutic targets for neurological diseases.
{"title":"Fibrinogen regulates microglial function through the JAK2/STAT3 signaling pathway","authors":"Xiaohui Li , Xiujuan Song , Fei Yi , Huiqing Hou","doi":"10.1016/j.cellimm.2025.104976","DOIUrl":"10.1016/j.cellimm.2025.104976","url":null,"abstract":"<div><h3>Background</h3><div>Neuroinflammation, a defining feature of numerous neurological disorders, arises predominantly from activating immune cells such as microglia, which play a critical role in maintaining homeostasis within the central nervous system. Microglial activation and polarization exhibit a dual nature, mediating both neuroprotective and neurotoxic effects. Fibrinogen, as a potent pro-inflammatory mediator, interacts with microglia and is implicated in the progression of various neurological conditions. This study investigates the effects of fibrinogen and the exogenous STAT3 inhibitor cryptotanshinone on primary microglial function.</div></div><div><h3>Methods</h3><div>Primary microglial cells were isolated from neonatal C57BL/6 mice and subsequently treated with fibrinogen and the STAT3 inhibitor cryptotanshinone. Inflammatory marker expression was quantified by quantitative polymerase chain reaction, while protein levels of JAK2 and STAT3 were determined using immunofluorescence and Western blot analysis.</div></div><div><h3>Results</h3><div>Fibrinogen exposure upregulated STAT3 and JAK2 phosphorylation in primary microglial cells. Cryptotanshinone treatment effectively attenuated STAT3 phosphorylation while concurrently downregulating JAK2 activation. Furthermore, fibrinogen significantly enhanced the release of pro-inflammatory cytokines, such as IL-6 and IL-1β, while the transcription levels of TGF-β remained unchanged.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that fibrinogen stimulates the production of pro-inflammatory cytokines in primary microglial cells by activating the JAK2/STAT3 signaling pathway. These findings provide mechanistic insights into fibrinogen-induced neuroinflammation and suggest potential therapeutic targets for neurological diseases.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"414 ","pages":"Article 104976"},"PeriodicalIF":3.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-20DOI: 10.1016/j.cellimm.2025.104973
Simon Fillatreau , Yi Hao
{"title":"Tribute to Mike Cancro – Former editor-in-chief at Cellular Immunology","authors":"Simon Fillatreau , Yi Hao","doi":"10.1016/j.cellimm.2025.104973","DOIUrl":"10.1016/j.cellimm.2025.104973","url":null,"abstract":"","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104973"},"PeriodicalIF":3.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteoblast differentiation is essential for fracture healing and bone regeneration. miR-324-5p has been implicated in osteoporosis, but its precise role in osteogenic differentiation remains unclear. We investigated the function and regulatory mechanisms of miR-324-5p in bone marrow mesenchymal stem cells (BMSCs).
Methods
RT-qPCR was used to assess miR-324-5p expression during osteogenic differentiation of BMSCs. ALP, Alizarin Red S (ARS), Oil Red O, and TRAP staining were performed to evaluate osteoblast, adipocyte, and osteoclast differentiation. Rat femoral fracture and calvarial bone defect models were established to assess in vivo bone regeneration. Methylated RNA immunoprecipitation (MeRIP) and luciferase reporter assays were used to investigate METTL3-mediated m6A modification of pri-miR-324-5p and its regulation of ELAVL1.
Results
miR-324-5p expression increased during osteogenic differentiation, and ALP and ARS staining confirmed enhanced osteoblast activity and mineralization following miR-324-5p overexpression. Meanwhile, Oil Red O staining showed reduced adipogenic differentiation, and TRAP staining demonstrated suppressed osteoclast formation. In vivo, miR-324-5p promoted bone healing, bone mass, and bone regeneration. Mechanistically, METTL3-mediated m6A modification facilitated pri-miR-324-5p maturation, positively regulating its expression. Additionally, miR-324-5p directly targeted ELAVL1, and ELAVL1 overexpression reversed the osteogenic effects of miR-324-5p.
Conclusion
The METTL3/miR-324-5p/ELAVL1 axis plays a crucial role in osteogenic differentiation and bone regeneration, providing new insights into m6A modification-driven osteogenesis.
{"title":"METTL3 facilitates osteoblast differentiation and bone regeneration via m6A-dependent maturation of pri-miR-324-5p","authors":"Jing Xiao , Zhiyuan Xu , Zhiwei Deng , Juntong Xie , Yiyan Qiu","doi":"10.1016/j.cellimm.2025.104974","DOIUrl":"10.1016/j.cellimm.2025.104974","url":null,"abstract":"<div><h3>Background</h3><div>Osteoblast differentiation is essential for fracture healing and bone regeneration. miR-324-5p has been implicated in osteoporosis, but its precise role in osteogenic differentiation remains unclear. We investigated the function and regulatory mechanisms of miR-324-5p in bone marrow mesenchymal stem cells (BMSCs).</div></div><div><h3>Methods</h3><div>RT-qPCR was used to assess miR-324-5p expression during osteogenic differentiation of BMSCs. ALP, Alizarin Red S (ARS), Oil Red O, and TRAP staining were performed to evaluate osteoblast, adipocyte, and osteoclast differentiation. Rat femoral fracture and calvarial bone defect models were established to assess in vivo bone regeneration. Methylated RNA immunoprecipitation (MeRIP) and luciferase reporter assays were used to investigate METTL3-mediated m6A modification of pri-miR-324-5p and its regulation of ELAVL1.</div></div><div><h3>Results</h3><div>miR-324-5p expression increased during osteogenic differentiation, and ALP and ARS staining confirmed enhanced osteoblast activity and mineralization following miR-324-5p overexpression. Meanwhile, Oil Red O staining showed reduced adipogenic differentiation, and TRAP staining demonstrated suppressed osteoclast formation. In vivo, miR-324-5p promoted bone healing, bone mass, and bone regeneration. Mechanistically, METTL3-mediated m6A modification facilitated pri-miR-324-5p maturation, positively regulating its expression. Additionally, miR-324-5p directly targeted ELAVL1, and ELAVL1 overexpression reversed the osteogenic effects of miR-324-5p.</div></div><div><h3>Conclusion</h3><div>The METTL3/miR-324-5p/ELAVL1 axis plays a crucial role in osteogenic differentiation and bone regeneration, providing new insights into m6A modification-driven osteogenesis.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104974"},"PeriodicalIF":3.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-13DOI: 10.1016/j.cellimm.2025.104972
Lihong Wu , Hang Xu , Xiaonan Zhang , Minghui Zhang , Yuting Xu , Qianyue Zhang , Huiying Tao , Changming Dong , Xinxin Zhang , Mingming Zhou , Jinbo Yang , Chunhua Lin , Qiaoling Song
Macrophages play a crucial role in antimicrobial host defense and those with differential maturation/differentiation status differ in inflammatory responses. Herein, GM-CSF and M-CSF primed mouse bone marrow derived macrophages (GM-BMDMs, GM and M-BMDMs, M), the well-established macrophage models in vitro, were utilized and their dynamic signaling changes in response to gram-negative bacteria component LPS treatment were analyzed using both 4D label-free proteomics and phosphoproteomics. Protein changes maintained relatively constant within or across GM and M macrophages post LPS challenge while phospho-protein exhibited more diverse and transient changes. Early induction of phospho-mediated GTPase activities, mRNA processing, and protein-mediated metabolic changes like oxidative phosphorylation (OXPHOS)/mitochondria function was identified at 1 h and maintained until 6 h post LPS treatment in GM and M while canonical TLR mediated MyD88-dependent and -independent pathways were activated at 3 and 6 h, individually at protein levels. Classical and novel phospho-sites for MyD88 and TRIF signaling pathways were also detected by phosphoproteomics. Comprehensively, the integrated protein and phospho-protein trend analysis was conducted and the core protein-phospho-protein network for the early phase actin reorganization, phagocytosis, and TLR signaling in both GM and M were presented. Taken together, these data described differences and similarities between these two types of macrophages in terms of their inflammatory responses to LPS.
{"title":"Integrated proteomics and phosphoproteomics profiling dynamic signaling networks underlying two distinct types of macrophage activation","authors":"Lihong Wu , Hang Xu , Xiaonan Zhang , Minghui Zhang , Yuting Xu , Qianyue Zhang , Huiying Tao , Changming Dong , Xinxin Zhang , Mingming Zhou , Jinbo Yang , Chunhua Lin , Qiaoling Song","doi":"10.1016/j.cellimm.2025.104972","DOIUrl":"10.1016/j.cellimm.2025.104972","url":null,"abstract":"<div><div>Macrophages play a crucial role in antimicrobial host defense and those with differential maturation/differentiation status differ in inflammatory responses. Herein, GM-CSF and M-CSF primed mouse bone marrow derived macrophages (GM-BMDMs, GM and M-BMDMs, M), the well-established macrophage models in vitro, were utilized and their dynamic signaling changes in response to gram-negative bacteria component LPS treatment were analyzed using both 4D label-free proteomics and phosphoproteomics. Protein changes maintained relatively constant within or across GM and M macrophages post LPS challenge while phospho-protein exhibited more diverse and transient changes. Early induction of phospho-mediated GTPase activities, mRNA processing, and protein-mediated metabolic changes like oxidative phosphorylation (OXPHOS)/mitochondria function was identified at 1 h and maintained until 6 h post LPS treatment in GM and M while canonical TLR mediated MyD88-dependent and -independent pathways were activated at 3 and 6 h, individually at protein levels. Classical and novel phospho-sites for MyD88 and TRIF signaling pathways were also detected by phosphoproteomics. Comprehensively, the integrated protein and phospho-protein trend analysis was conducted and the core protein-phospho-protein network for the early phase actin reorganization, phagocytosis, and TLR signaling in both GM and M were presented. Taken together, these data described differences and similarities between these two types of macrophages in terms of their inflammatory responses to LPS.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104972"},"PeriodicalIF":3.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-10DOI: 10.1016/j.cellimm.2025.104971
Yibing Yu , Huanbin Yang , Hao Wang , Fei Xiao
Immune cells play active roles in the surveillance and control of colorectal cancer (CRC) progression. Natural killer (NK) cells are powerful anti-tumor effector cells but their regulatory mechanisms in the CRC tissues have not been thoroughly elucidated. In this research using a murine inflammatory colorectal cancer model, we characterized the phenotype and function of NK cells. We found signs of NK cell dysfunction in CRC tissues, including up-regulation of exhaustion markers, down-regulation of activating receptors, deficiencies in degranulation and cytokine expression, and weak cytolytic effect. Interestingly, zinc finger protein 217 (ZNF217), a transcription repressor, was significantly up-regulated in CRC-associated NK cells. In vitro assays revealed that ZNF217 knockdown promoted NK cell cytolytic activity, implying that ZNF217 is an inhibitory factor of NK cell function. Adoptive transfer assays indicated that ZNF217 knockdown also resulted in enhancement of NK cell function in vivo and subsequently suppressed CRC development. Furthermore, hypoxia rather than exhaustion up-regulated ZNF217 expression in NK cells. ZNF217 knockdown promoted NK cell resistance to hypoxia-mediated NK cell dysfunction. Therefore, we discovered a novel regulatory factor of NK cell dysfunction during CRC development.
{"title":"Zinc finger protein 217 contributes to natural killer cell dysfunction in murine colorectal cancer","authors":"Yibing Yu , Huanbin Yang , Hao Wang , Fei Xiao","doi":"10.1016/j.cellimm.2025.104971","DOIUrl":"10.1016/j.cellimm.2025.104971","url":null,"abstract":"<div><div>Immune cells play active roles in the surveillance and control of colorectal cancer (CRC) progression. Natural killer (NK) cells are powerful anti-tumor effector cells but their regulatory mechanisms in the CRC tissues have not been thoroughly elucidated. In this research using a murine inflammatory colorectal cancer model, we characterized the phenotype and function of NK cells. We found signs of NK cell dysfunction in CRC tissues, including up-regulation of exhaustion markers, down-regulation of activating receptors, deficiencies in degranulation and cytokine expression, and weak cytolytic effect. Interestingly, zinc finger protein 217 (ZNF217), a transcription repressor, was significantly up-regulated in CRC-associated NK cells. <em>In vitro</em> assays revealed that ZNF217 knockdown promoted NK cell cytolytic activity, implying that ZNF217 is an inhibitory factor of NK cell function. Adoptive transfer assays indicated that ZNF217 knockdown also resulted in enhancement of NK cell function <em>in vivo</em> and subsequently suppressed CRC development. Furthermore, hypoxia rather than exhaustion up-regulated ZNF217 expression in NK cells. ZNF217 knockdown promoted NK cell resistance to hypoxia-mediated NK cell dysfunction. Therefore, we discovered a novel regulatory factor of NK cell dysfunction during CRC development.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104971"},"PeriodicalIF":3.7,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-09DOI: 10.1016/j.cellimm.2025.104963
Fatemeh Hesampour , Charles N. Bernstein , Jean-Eric Ghia
Recent recognition of the intricate nervous-immune system interplay has prompted research into the specific cellular components involved in these interactions. Emerging evidence suggests that immune and neural cells collaborate within distinct units and act in concert to regulate tissue function and provide protection. These specialized neuro-immune cell units have been identified in diverse body tissues, ranging from lymphoid organs to the bone marrow and mucosal barriers. Their significance has become increasingly apparent as they are recognized as pivotal regulators influencing a broad spectrum of physiological and pathological processes. This recognition extends to critical roles in hematopoiesis, organ function, inflammatory responses, and intricate tissue repair processes. This review explores the bidirectional communication between the nervous and immune systems. The focus is on understanding the profound impact of this communication on immune cells within key anatomical sites, such as the bone marrow, gastrointestinal tract, and lymphoid organs. By examining these interactions, this review aims to shed light on how this intricate network operates under normal and pathological conditions, offering insights into the mechanisms underlying health and disease.
{"title":"Investigating the effect of neuro-immune communication on immune responses in health and disease: Exploring immunological disorders","authors":"Fatemeh Hesampour , Charles N. Bernstein , Jean-Eric Ghia","doi":"10.1016/j.cellimm.2025.104963","DOIUrl":"10.1016/j.cellimm.2025.104963","url":null,"abstract":"<div><div>Recent recognition of the intricate nervous-immune system interplay has prompted research into the specific cellular components involved in these interactions. Emerging evidence suggests that immune and neural cells collaborate within distinct units and act in concert to regulate tissue function and provide protection. These specialized neuro-immune cell units have been identified in diverse body tissues, ranging from lymphoid organs to the bone marrow and mucosal barriers. Their significance has become increasingly apparent as they are recognized as pivotal regulators influencing a broad spectrum of physiological and pathological processes. This recognition extends to critical roles in hematopoiesis, organ function, inflammatory responses, and intricate tissue repair processes. This review explores the bidirectional communication between the nervous and immune systems. The focus is on understanding the profound impact of this communication on immune cells within key anatomical sites, such as the bone marrow, gastrointestinal tract, and lymphoid organs. By examining these interactions, this review aims to shed light on how this intricate network operates under normal and pathological conditions, offering insights into the mechanisms underlying health and disease.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104963"},"PeriodicalIF":3.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-09DOI: 10.1016/j.cellimm.2025.104960
Jiangning Xiang, Lin Yao, Shan Wang, Lei Zhao, Jing Yu
Exosomes play an important role in the metastatic microenvironment, acting as a transmission belt that facilitates intercellular communication. By delivering proteins, nucleic acids, and other substances in the exosomes, they can change the function of the receptor target cells, change the microenvironment of the metastatic site, and promote the colonization of the tumor cells, thus promoting cancer metastasis. The interaction between tumor cells and the surrounding microenvironment is complex, with exosomes serving as key facilitators of crosstalk between the primary tumor microenvironment and the pre-metastasis microenvironment. Despite many current studies to explore exosomes, we still do not have a detailed understanding of the role and mechanism of exosomes in the pre-metastatic immune microenvironment, and there are many challenges in the clinical application of exosomes. In this paper, we summarize the role of exosomes in regulating the pre-metastatic immune microenvironment and its mechanism, focusing on how exosomes regulate the function of immune cells in the pre-metastatic microenvironment to promote tumor metastasis. In addition, the potential application of exosomes in tumor immunotherapy and strategies for targeting exosomes are discussed. This will contribute to the immunotherapy of cancer metastasis and promote the clinical application of exosomes.
{"title":"Progress of exosomes in regulating tumor metastasis by remodeling the pre-metastatic immune microenvironment","authors":"Jiangning Xiang, Lin Yao, Shan Wang, Lei Zhao, Jing Yu","doi":"10.1016/j.cellimm.2025.104960","DOIUrl":"10.1016/j.cellimm.2025.104960","url":null,"abstract":"<div><div>Exosomes play an important role in the metastatic microenvironment, acting as a transmission belt that facilitates intercellular communication. By delivering proteins, nucleic acids, and other substances in the exosomes, they can change the function of the receptor target cells, change the microenvironment of the metastatic site, and promote the colonization of the tumor cells, thus promoting cancer metastasis. The interaction between tumor cells and the surrounding microenvironment is complex, with exosomes serving as key facilitators of crosstalk between the primary tumor microenvironment and the pre-metastasis microenvironment. Despite many current studies to explore exosomes, we still do not have a detailed understanding of the role and mechanism of exosomes in the pre-metastatic immune microenvironment, and there are many challenges in the clinical application of exosomes. In this paper, we summarize the role of exosomes in regulating the pre-metastatic immune microenvironment and its mechanism, focusing on how exosomes regulate the function of immune cells in the pre-metastatic microenvironment to promote tumor metastasis. In addition, the potential application of exosomes in tumor immunotherapy and strategies for targeting exosomes are discussed. This will contribute to the immunotherapy of cancer metastasis and promote the clinical application of exosomes.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104960"},"PeriodicalIF":3.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beta-2-microglobulin (β2m) is a component of the major histocompatibility complex class I. β2m is released into cellular fluids in response to various stimuli, including pro-inflammatory cytokines. Elevated β2m levels have been found associated with autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Crohn's disease, as well as in various hematological cancers and viral infections. Despite an established correlation between immune activation of especially monocytes and macrophages, and circulating β2m levels, the causative relationship remains unclear. Here, we investigate the effects of exogenous β2m and a complement C1s cleaved form, dK58β2m, on two murine macrophage-like cell lines J774 and RAW. We demonstrate that β2m, and to a greater extent dK58β2m, can affect mitochondrial activity. Furthermore, the presence of IFN-γ amplifies the effect, causing altered bioenergetics, and increased production of mitochondrial reactive oxygen species and nitric oxide. In addition, we found activation of the cGAS-STING pathway by β2m and dK58β2m in the presence of IFN-γ. Only dK58β2m in combination with IFN-γ caused apoptosis and cell death. Our findings highlight the modular nature of a β2m-induced macrophage response, potentiated by dK58β2m and IFN-γ, and provide information on the underlying mechanisms responsible for the immune activation properties of β2m.
{"title":"Modular activation of macrophage-like cells by beta-2-microglobulin via mitochondria and the cGAS-STING pathway","authors":"Josefine Kofoed Corneliussen , Helena Borland Madsen , Nadia Thaulov Zelander , Mogens Holst Nissen , Claus Desler","doi":"10.1016/j.cellimm.2025.104962","DOIUrl":"10.1016/j.cellimm.2025.104962","url":null,"abstract":"<div><div>Beta-2-microglobulin (β2m) is a component of the major histocompatibility complex class I. β2m is released into cellular fluids in response to various stimuli, including pro-inflammatory cytokines. Elevated β2m levels have been found associated with autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Crohn's disease, as well as in various hematological cancers and viral infections. Despite an established correlation between immune activation of especially monocytes and macrophages, and circulating β2m levels, the causative relationship remains unclear. Here, we investigate the effects of exogenous β2m and a complement C1s cleaved form, dK58β2m, on two murine macrophage-like cell lines J774 and RAW. We demonstrate that β2m, and to a greater extent dK58β2m, can affect mitochondrial activity. Furthermore, the presence of IFN-γ amplifies the effect, causing altered bioenergetics, and increased production of mitochondrial reactive oxygen species and nitric oxide. In addition, we found activation of the cGAS-STING pathway by β2m and dK58β2m in the presence of IFN-γ. Only dK58β2m in combination with IFN-γ caused apoptosis and cell death. Our findings highlight the modular nature of a β2m-induced macrophage response, potentiated by dK58β2m and IFN-γ, and provide information on the underlying mechanisms responsible for the immune activation properties of β2m.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104962"},"PeriodicalIF":3.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.cellimm.2025.104959
Bhatnagar Megha , K.L. Milan , M. Anuradha , Kunka Mohanram Ramkumar
Inflammasomes are multiprotein complexes that initiate inflammatory responses by activating pro-inflammatory cytokines, playing a crucial role in innate immunity. However, their dysregulation can lead to excessive inflammation, particularly in conditions like gestational diabetes mellitus (GDM), where placental inflammation may adversely affect fetal development and increase the risk of complications. NEK7 (NIMA-related kinase 7) has been identified as a key mediator in inflammasome activation, facilitating the complex assembly and amplifying inflammatory responses. This study aims to investigate the regulatory role of miRNA in inflammasome-mediated placental inflammation through its interaction with NEK7 in the pathophysiology of GDM. In-silico analysis identified that NEK7 is a direct target of miR-186-5p, while PCR analysis demonstrated a significant loss of miR-186-5p expression in GDM placental tissues. Further, the expressions of NEK7, NLRP1, NLRP3, Caspase 1 along with the inflammatory cytokines were significantly elevated in GDM placenta. Furthermore, the correlation analysis demonstrated a significant negative correlation between miR-186-5p and NEK7 expression levels, suggesting that the loss of miR-186-5p may contribute to inflammasome mediated placental inflammation in GDM. Additionally, the overexpression of miR-186-5p decreased the high glucose induced inflammation and the expressions of NEK7, NLRP1 and NLRP3 in BeWo cell line. Therefore, this study concludes that miR-186-5p may attenuate the activation of inflammasome and regulate inflammation via NEK7 in the progression of GDM. Understanding these molecular mechanisms offers valuable insights into potential therapeutic targets aimed at improving pregnancy outcomes in GDM.
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