Pub Date : 2024-09-30DOI: 10.1038/s41423-024-01217-y
Xiaoxia Wu, Xiaoming Zhao, Fang Li, Yang Wang, Yangjing Ou, Haiwei Zhang, Xiaoming Li, Xuanhui Wu, Lingxia Wang, Ming Li, Yue Zhang, Jianling Liu, Mingyan Xing, Han Liu, Yongchang Tan, Yangyang Wang, Yangyang Xie, Hanwen Zhang, Yan Luo, Hong Li, Jing Wang, Liming Sun, Yu Li, Haibing Zhang
The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
{"title":"MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome","authors":"Xiaoxia Wu, Xiaoming Zhao, Fang Li, Yang Wang, Yangjing Ou, Haiwei Zhang, Xiaoming Li, Xuanhui Wu, Lingxia Wang, Ming Li, Yue Zhang, Jianling Liu, Mingyan Xing, Han Liu, Yongchang Tan, Yangyang Wang, Yangyang Xie, Hanwen Zhang, Yan Luo, Hong Li, Jing Wang, Liming Sun, Yu Li, Haibing Zhang","doi":"10.1038/s41423-024-01217-y","DOIUrl":"10.1038/s41423-024-01217-y","url":null,"abstract":"The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1309-1321"},"PeriodicalIF":21.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1038/s41423-024-01215-0
Shuai Wang, Lijun Meng, Nan Xu, Huan Chen, Zhaofeng Xiao, Di Lu, Xiaohui Fan, Limin Xia, Jun Chen, Shusen Zheng, Qiang Wei, Xuyong Wei, Xiao Xu
Hepatocellular carcinoma (HCC) is a highly malignant tumor with significant global health implications. The role of CD4+ T cells, particularly conventional CD4+ T cells (Tconvs), in HCC progression remains unexplored. Furthermore, epigenetic factors are crucial in immune regulation, yet their specific role in HCC-infiltrating Tconv cells remains elusive. This study elucidates the role of MATR3, an epigenetic regulator, in modulating Tconv activity and immune evasion within the HCC microenvironment. Reanalysis of the scRNA-seq data revealed that early activation of CD4+ T cells is crucial for establishing an antitumor immune response. In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8+ T-cell activation. Screening identified MATR3 as a critical regulator of Tconv function, which is necessary for antitumour activity but harmful when overexpressed. Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region, leading to aberrant transcriptional changes. In summary, MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity, suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC.
{"title":"Hepatocellular carcinoma-specific epigenetic checkpoints bidirectionally regulate the antitumor immunity of CD4 + T cells","authors":"Shuai Wang, Lijun Meng, Nan Xu, Huan Chen, Zhaofeng Xiao, Di Lu, Xiaohui Fan, Limin Xia, Jun Chen, Shusen Zheng, Qiang Wei, Xuyong Wei, Xiao Xu","doi":"10.1038/s41423-024-01215-0","DOIUrl":"10.1038/s41423-024-01215-0","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a highly malignant tumor with significant global health implications. The role of CD4+ T cells, particularly conventional CD4+ T cells (Tconvs), in HCC progression remains unexplored. Furthermore, epigenetic factors are crucial in immune regulation, yet their specific role in HCC-infiltrating Tconv cells remains elusive. This study elucidates the role of MATR3, an epigenetic regulator, in modulating Tconv activity and immune evasion within the HCC microenvironment. Reanalysis of the scRNA-seq data revealed that early activation of CD4+ T cells is crucial for establishing an antitumor immune response. In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8+ T-cell activation. Screening identified MATR3 as a critical regulator of Tconv function, which is necessary for antitumour activity but harmful when overexpressed. Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region, leading to aberrant transcriptional changes. In summary, MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity, suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1296-1308"},"PeriodicalIF":21.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The transcription factor Pax5 activates genes essential for B-cell development and function. However, the regulation of Pax5 expression remains elusive. The adaptor Rack1 can interact with multiple transcription factors and modulate their activation and/or stability. However, its role in the transcriptional control of B-cell fates is largely unknown. Here, we show that CD19-driven Rack1 deficiency leads to pro-B accumulation and a simultaneous reduction in B cells at later developmental stages. The generation of bone marrow chimeras indicates a cell-intrinsic role of Rack1 in B-cell homeostasis. Moreover, Rack1 augments BCR and TLR signaling in mature B cells. On the basis of the aberrant expression of Pax5-regulated genes, including CD19, upon Rack1 deficiency, further exploration revealed that Rack1 maintains the protein level of Pax5 through direct interaction and consequently prevents Pax5 ubiquitination. Accordingly, Mb1-driven Rack1 deficiency almost completely blocks B-cell development at the pro-B-cell stage. Ectopic expression of Pax5 in Rack1-deficient pro-B cells partially rescues B-cell development. Thus, Rack1 regulates B-cell development and function through, at least partially, binding to and stabilizing Pax5.
转录因子 Pax5 可激活 B 细胞发育和功能所必需的基因。然而，Pax5 的表达调控仍然难以捉摸。适配体 Rack1 可与多种转录因子相互作用，并调节它们的激活和/或稳定性。然而，它在B细胞命运转录调控中的作用在很大程度上还不为人所知。在这里，我们发现 CD19 驱动的 Rack1 缺乏会导致亲 B 细胞的积累，并同时导致发育后期 B 细胞的减少。骨髓嵌合体的产生表明 Rack1 在 B 细胞稳态中发挥着细胞内在的作用。此外，Rack1 还能增强成熟 B 细胞中的 BCR 和 TLR 信号转导。基于 Rack1 缺乏时包括 CD19 在内的 Pax5 调控基因的异常表达，进一步研究发现 Rack1 通过直接相互作用维持 Pax5 的蛋白水平，从而阻止 Pax5 泛素化。因此，Mb1 驱动的 Rack1 缺乏几乎完全阻断了前 B 细胞阶段的 B 细胞发育。在 Rack1 缺乏的原 B 细胞中异位表达 Pax5 可部分挽救 B 细胞的发育。因此，Rack1 至少部分通过与 Pax5 结合并稳定 Pax5 来调节 B 细胞的发育和功能。
{"title":"Rack1 regulates B-cell development and function by binding to and stabilizing the transcription factor Pax5","authors":"Xueting Zhang, Chenke Ma, Yuchen Lu, Jing Wang, Hongfang Yun, Hui Jiang, Mengyao Wu, Xiaoyao Feng, Wenbin Gai, Guanglei Xu, Hongbin Deng, Jiannan Feng, Wanli Liu, Taoxing Shi, Qianqian Cheng, Jiyan Zhang","doi":"10.1038/s41423-024-01213-2","DOIUrl":"10.1038/s41423-024-01213-2","url":null,"abstract":"The transcription factor Pax5 activates genes essential for B-cell development and function. However, the regulation of Pax5 expression remains elusive. The adaptor Rack1 can interact with multiple transcription factors and modulate their activation and/or stability. However, its role in the transcriptional control of B-cell fates is largely unknown. Here, we show that CD19-driven Rack1 deficiency leads to pro-B accumulation and a simultaneous reduction in B cells at later developmental stages. The generation of bone marrow chimeras indicates a cell-intrinsic role of Rack1 in B-cell homeostasis. Moreover, Rack1 augments BCR and TLR signaling in mature B cells. On the basis of the aberrant expression of Pax5-regulated genes, including CD19, upon Rack1 deficiency, further exploration revealed that Rack1 maintains the protein level of Pax5 through direct interaction and consequently prevents Pax5 ubiquitination. Accordingly, Mb1-driven Rack1 deficiency almost completely blocks B-cell development at the pro-B-cell stage. Ectopic expression of Pax5 in Rack1-deficient pro-B cells partially rescues B-cell development. Thus, Rack1 regulates B-cell development and function through, at least partially, binding to and stabilizing Pax5.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1282-1295"},"PeriodicalIF":21.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.
剪接体功能障碍和 RNA 剪接异常凸显了尚未解决的炎症和免疫发病机制。在这里，我们揭示了类风湿性关节炎（RA）发病机制中通过剪接体对 mRNA 剪接的误调。其中，RNA 结合基调蛋白 25（RBM25）表达的减少被确定为 RA 患者和实验性关节炎小鼠的主要致病因素，它通过增加促炎介质的产生和巨噬细胞中的高炎症性增加而致病。对 RBM25 缺陷小鼠巨噬细胞的多组学分析表明，促炎基因（包括 Il1b、Il6 和 Cxcl10）的转录增强与组蛋白 3 赖氨酸 9 乙酰化（H3K9ac）和 H3K27ac 修饰以及缺氧诱导因子-1α（HIF-1α）活性有关。此外，RBM25直接与ATP柠檬酸裂解酶（Acly）前mRNA的第14个外显子结合并介导其跳过，从而产生了两种不同的Acly异构体，即Acly长（Acly L）和Acly短（Acly S）。在促炎巨噬细胞中，Acly L 在赖氨酸 918/995 上发生蛋白乳化，而 Acly S 则没有，这影响了它对代谢底物的亲和力和随后的代谢活性。RBM25 缺乏会显著增加 Acly S 异构体的表达，从而提高糖酵解和乙酰-CoA 的产生，促进表观遗传重塑、巨噬细胞过度活化和组织炎症损伤。最后，巨噬细胞特异性缺失 RBM25 会导致炎症，包括小鼠各种关节的自发性关节炎和多个器官的炎症，而药物抑制 Acly 可以缓解这些炎症。总之，靶向RBM25-Acly剪接轴是调节自身免疫性关节炎和衰老相关炎症中巨噬细胞反应的一种潜在策略。
{"title":"RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring","authors":"Yunkai Zhang, Ying Gao, Yujia Wang, Yuyu Jiang, Yan Xiang, Xiaohui Wang, Zeting Wang, Yingying Ding, Huiying Chen, Bing Rui, Wanwan Huai, Boyu Cai, Xiaomeng Ren, Feng Ma, Sheng Xu, Zhenzhen Zhan, Xingguang Liu","doi":"10.1038/s41423-024-01212-3","DOIUrl":"10.1038/s41423-024-01212-3","url":null,"abstract":"Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1231-1250"},"PeriodicalIF":21.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1038/s41423-024-01211-4
Fan Xiao, Dongmei Zhou, Meng Cao, Haijing Wu, Chunxing Zheng, Ke Rui, Liwei Lu
{"title":"The emerging roles of B cells in cancer development","authors":"Fan Xiao, Dongmei Zhou, Meng Cao, Haijing Wu, Chunxing Zheng, Ke Rui, Liwei Lu","doi":"10.1038/s41423-024-01211-4","DOIUrl":"10.1038/s41423-024-01211-4","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1180-1182"},"PeriodicalIF":21.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4+ T cells in the presence of IL-4 and transforming growth factor-beta (TGF-β); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-β–driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis. On the basis of these findings, we hypothesized that lipid metabolism may also be important for Th9 cell differentiation. We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β–SMAD signaling pathways. Upon adoptive transfer, ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma. Together, our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.
{"title":"Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling","authors":"Takahiro Nakajima, Toshio Kanno, Yuki Ueda, Keisuke Miyako, Takeru Endo, Souta Yoshida, Satoru Yokoyama, Hikari K. Asou, Kazuko Yamada, Kazutaka Ikeda, Yosuke Togashi, Yusuke Endo","doi":"10.1038/s41423-024-01209-y","DOIUrl":"10.1038/s41423-024-01209-y","url":null,"abstract":"T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4+ T cells in the presence of IL-4 and transforming growth factor-beta (TGF-β); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-β–driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis. On the basis of these findings, we hypothesized that lipid metabolism may also be important for Th9 cell differentiation. We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β–SMAD signaling pathways. Upon adoptive transfer, ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma. Together, our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1266-1281"},"PeriodicalIF":21.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01209-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency. Mitochondria, which feature prokaryotic characteristics and contain various damage-associated molecular patterns (DAMPs), are easily taken up by phagocytes and simultaneously activate innate immunity. In the current study, we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine. Ovalbumin (OVA) and tyrosinase-related protein 2 (TRP2) were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides. The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2. Engineered OVA- and TRP2-containing mitochondria (OVA-MITO and TRP2-MITO) were extracted and evaluated as potential cancer vaccines. Impressively, the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models. Mechanistically, OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells (DCs) and induced a tumor-specific cell-mediated immunity. Moreover, DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist, namely, cardiolipin derived from the mitochondrial membrane. The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery, which could preferably target local dendritic cells and exert strong adaptive cellular immunity. This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.
抗原递送方式的优选以及充足的佐剂有利于提高疫苗的效率。线粒体具有原核生物特征，含有各种损伤相关分子模式（DAMPs），很容易被吞噬细胞吸收，同时激活先天免疫。在本研究中，我们建立了线粒体工程平台，用于产生富含抗原的线粒体作为癌症疫苗。以卵清蛋白（OVA）和酪氨酸酶相关蛋白 2（TRP2）为模型抗原，合成具有线粒体定位信号肽的融合蛋白。然后利用慢病毒感染系统生产含有 OVA 或 TRP2 的线粒体疫苗。提取了含有 OVA 和 TRP2 的工程线粒体（OVA-MITO 和 TRP2-MITO），并将其作为潜在的癌症疫苗进行评估。令人印象深刻的是，工程线粒体疫苗在小鼠肿瘤模型中作为预防性和治疗性疫苗使用时显示出高效的抗肿瘤效果。从机理上讲，OVA-MITO 和 TRP2-MITO 能有效招募和激活树突状细胞（DCs），诱导肿瘤特异性细胞介导免疫。此外，线粒体疫苗对 DC 的激活主要涉及 TLR2 通路及其脂质激动剂，即来自线粒体膜的心磷脂。研究结果表明，线粒体是一种天然的载体，充满了用于递送抗原的免疫刺激物质，可优先靶向局部树突状细胞，发挥强大的适应性细胞免疫作用。这项概念验证研究为利用携带可改变抗原的工程线粒体构建用于癌症和其他疾病的疫苗建立了一个通用平台。
{"title":"Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform","authors":"Jingwen Luo, Fei Mo, Zhe Zhang, Weiqi Hong, Tianxia Lan, Yuan Cheng, Chunju Fang, Zhenfei Bi, Furong Qin, Jingyun Yang, Ziqi Zhang, Xue Li, Haiying Que, Jiayu Wang, Siyuan Chen, Yiming Wu, Li Yang, Jiong Li, Wei Wang, Chong Chen, Xiawei Wei","doi":"10.1038/s41423-024-01203-4","DOIUrl":"10.1038/s41423-024-01203-4","url":null,"abstract":"The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency. Mitochondria, which feature prokaryotic characteristics and contain various damage-associated molecular patterns (DAMPs), are easily taken up by phagocytes and simultaneously activate innate immunity. In the current study, we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine. Ovalbumin (OVA) and tyrosinase-related protein 2 (TRP2) were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides. The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2. Engineered OVA- and TRP2-containing mitochondria (OVA-MITO and TRP2-MITO) were extracted and evaluated as potential cancer vaccines. Impressively, the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models. Mechanistically, OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells (DCs) and induced a tumor-specific cell-mediated immunity. Moreover, DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist, namely, cardiolipin derived from the mitochondrial membrane. The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery, which could preferably target local dendritic cells and exert strong adaptive cellular immunity. This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1251-1265"},"PeriodicalIF":21.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01203-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1038/s41423-024-01208-z
Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Pedram Shafiei-Jahani, Mohammad Hossein Kazemi, Xin Li, Stephen Shen, Richard Barbers, Omid Akbari
Group-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. The activation and function of ILC2s are regulated by various activating and inhibitory molecules, with their balance determining the severity of allergic responses. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the function of SIRPα in ILC2-mediated AHR, we combined multiple approaches including genetically modified mouse models and adoptive transfer experiments in murine models of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement of SIRPα with CD47 reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type 2 cytokines. Additionally, our studies have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of human CD47-Fc effectively suppresses the effector function and cytokine production. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviates AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.
{"title":"SIRPα engagement regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism","authors":"Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Pedram Shafiei-Jahani, Mohammad Hossein Kazemi, Xin Li, Stephen Shen, Richard Barbers, Omid Akbari","doi":"10.1038/s41423-024-01208-z","DOIUrl":"10.1038/s41423-024-01208-z","url":null,"abstract":"Group-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. The activation and function of ILC2s are regulated by various activating and inhibitory molecules, with their balance determining the severity of allergic responses. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the function of SIRPα in ILC2-mediated AHR, we combined multiple approaches including genetically modified mouse models and adoptive transfer experiments in murine models of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement of SIRPα with CD47 reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type 2 cytokines. Additionally, our studies have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of human CD47-Fc effectively suppresses the effector function and cytokine production. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviates AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 10","pages":"1158-1174"},"PeriodicalIF":21.8,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01208-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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