Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps (NETs). However, the substrates of PAD4 and its exact role in inflammatory bowel disease (IBD) remain unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD. Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium (DSS)-induced colitis mouse model. scRNA-seq analysis revealed significant alterations in intestinal cell populations, with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion. Gene expression analysis highlighted pathways related to inflammation and epithelial cell function. Furthermore, we found that neutrophil-derived extracellular vesicles (EVs) carrying PAD4 were secreted into intestinal epithelial cells (IECs). Within IECs, PAD4 citrullinates mitochondrial creatine kinase 1 (CKMT1) at the R242 site, leading to reduced CKMT1 protein stability via the autophagy pathway. This action compromises mitochondrial homeostasis, impairs intestinal barrier integrity, and induces IECs apoptosis. IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis. Clinical analysis of IBD patients revealed elevated levels of PAD4, increased CKMT1 citrullination, and decreased CKMT1 expression. In summary, our findings highlight the crucial role of PAD4 in IBD, where it modulates IECs plasticity via CKMT1 citrullination, suggesting that PAD4 may be a potential therapeutic target for IBD.
{"title":"Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease","authors":"Shuling Wang, Yihang Song, Zhijie Wang, Xin Chang, Haicong Wu, Ziwei Yan, Jiayi Wu, Zixuan He, Le Kang, Wenjun Hu, Tian Xia, Zhaoshen Li, Xingxing Ren, Yu Bai","doi":"10.1038/s41423-024-01158-6","DOIUrl":"10.1038/s41423-024-01158-6","url":null,"abstract":"Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps (NETs). However, the substrates of PAD4 and its exact role in inflammatory bowel disease (IBD) remain unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD. Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium (DSS)-induced colitis mouse model. scRNA-seq analysis revealed significant alterations in intestinal cell populations, with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion. Gene expression analysis highlighted pathways related to inflammation and epithelial cell function. Furthermore, we found that neutrophil-derived extracellular vesicles (EVs) carrying PAD4 were secreted into intestinal epithelial cells (IECs). Within IECs, PAD4 citrullinates mitochondrial creatine kinase 1 (CKMT1) at the R242 site, leading to reduced CKMT1 protein stability via the autophagy pathway. This action compromises mitochondrial homeostasis, impairs intestinal barrier integrity, and induces IECs apoptosis. IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis. Clinical analysis of IBD patients revealed elevated levels of PAD4, increased CKMT1 citrullination, and decreased CKMT1 expression. In summary, our findings highlight the crucial role of PAD4 in IBD, where it modulates IECs plasticity via CKMT1 citrullination, suggesting that PAD4 may be a potential therapeutic target for IBD.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140888316","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}
{"title":"Distinct palmitoylation of Foxp3 regulates the function of regulatory T cells via palmitoyltransferases","authors":"Binhui Zhou, Mengjie Zhang, Haoyuan Ma, Ying Wang, Juanjuan Qiu, Yang Liu, Liaoxun Lu, Tianhan Li, Lichen Zhang, Rong Huang, Yanrong Gu, Eryan Kong, Yinming Liang","doi":"10.1038/s41423-024-01166-6","DOIUrl":"10.1038/s41423-024-01166-6","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140888390","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 : 2024-04-30DOI: 10.1038/s41423-024-01150-0
Lina Wang, Shushu Yang, Gaohui Zhu, Jie Li, Gang Meng, Xiaoling Chen, Mengjun Zhang, Shufeng Wang, Xiangqian Li, Yu Pan, Yi Huang, Li Wang, Yuzhang Wu
Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in β-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet β-cells under steady and ERS conditions and found that ERS reshaped the MIP of β-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting β-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.
自反应性 CD8+ T 细胞在 1 型糖尿病（T1D）中起着关键作用，但激活自反应性 CD8+ T 细胞的抗原谱仍不清楚。内质网应激（ERS）与β细胞自身抗原的产生有关。在这里，我们分析了胰岛β细胞在稳定和ERS条件下的主要组织相容性复合体I类（MHC-I）相关免疫肽组（MIP），发现ERS重塑了β细胞的MIP，促进了一组常规自身肽的MHC-I呈现。其中，OTUB258-66表现出免疫优势，相应的自反应CD8+ T细胞对非肥胖糖尿病（NOD）小鼠具有致糖尿病作用。高糖摄入会上调胰腺 OTUB2 的表达，并增强 NOD 小鼠对 OTUB258-66 特异性 CD8+ T 细胞的反应。重复给药 OTUB258-66 能显著降低 NOD 小鼠 T1D 的发病率。有趣的是，T1D 患者的外周血单核细胞（PBMCs）对人 OTUB2 肽的 IFN-γ 反应呈阳性，而健康对照组则没有。这项研究不仅为 ERS 在促进以 β 细胞为靶点的自身免疫中的作用提供了新的解释，还为预防和治疗 T1D 提供了潜在的靶点。这些数据可通过蛋白质组交换（ProteomeXchange）获得，其标识符为 PXD041227。
{"title":"Immunopeptidome mining reveals a novel ERS-induced target in T1D","authors":"Lina Wang, Shushu Yang, Gaohui Zhu, Jie Li, Gang Meng, Xiaoling Chen, Mengjun Zhang, Shufeng Wang, Xiangqian Li, Yu Pan, Yi Huang, Li Wang, Yuzhang Wu","doi":"10.1038/s41423-024-01150-0","DOIUrl":"10.1038/s41423-024-01150-0","url":null,"abstract":"Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in β-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet β-cells under steady and ERS conditions and found that ERS reshaped the MIP of β-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting β-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831207","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 : 2024-04-29DOI: 10.1038/s41423-024-01161-x
Sytse J. Piersma
Innate lymphocytes (ILCs) rapidly respond to and protect against invading pathogens and cancer. ILCs include natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells and include type I, type II, and type III immune cells. While NK cells have been well recognized for their role in antiviral immunity, other ILC subtypes are emerging as players in antiviral defense. Each ILC subset has specialized functions that uniquely impact the antiviral immunity and health of the host depending on the tissue microenvironment. This review focuses on the specialized functions of each ILC subtype and their roles in antiviral immune responses across tissues. Several viruses within infection-prone tissues will be highlighted to provide an overview of the extent of the ILC immunity within tissues and emphasize common versus virus-specific responses.
先天性淋巴细胞（ILCs）能对入侵的病原体和癌症迅速做出反应并提供保护。先天性淋巴细胞包括自然杀伤（NK）细胞、ILC1、ILC2、ILC3 和淋巴组织诱导（LTi）细胞，并包括 I 型、II 型和 III 型免疫细胞。NK 细胞在抗病毒免疫中的作用已得到广泛认可，而其他 ILC 亚型也正在成为抗病毒防御中的角色。每个 ILC 亚型都具有特殊的功能，根据组织微环境的不同，对宿主的抗病毒免疫和健康产生独特的影响。本综述将重点介绍每种 ILC 亚型的特殊功能及其在不同组织的抗病毒免疫反应中的作用。将重点介绍易感染组织中的几种病毒，以概述组织内 ILC 免疫的程度，并强调常见反应与病毒特异性反应的区别。
{"title":"Tissue-specific features of innate lymphoid cells in antiviral defense","authors":"Sytse J. Piersma","doi":"10.1038/s41423-024-01161-x","DOIUrl":"10.1038/s41423-024-01161-x","url":null,"abstract":"Innate lymphocytes (ILCs) rapidly respond to and protect against invading pathogens and cancer. ILCs include natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells and include type I, type II, and type III immune cells. While NK cells have been well recognized for their role in antiviral immunity, other ILC subtypes are emerging as players in antiviral defense. Each ILC subset has specialized functions that uniquely impact the antiviral immunity and health of the host depending on the tissue microenvironment. This review focuses on the specialized functions of each ILC subtype and their roles in antiviral immune responses across tissues. Several viruses within infection-prone tissues will be highlighted to provide an overview of the extent of the ILC immunity within tissues and emphasize common versus virus-specific responses.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01161-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140812889","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}
Inflammatory bowel disease (IBD) is prevalent, and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood. In this study, we discovered that increased expression of methyltransferase-like 3 (METTL3) in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate (DSS)-induced colitis. Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase (PGP), which resulted in glucose metabolism reprogramming and the suppression of CD4+ T helper 1 (Th1) cell differentiation. Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms. In addition, we developed two potent small molecule METTL3 inhibitors, namely, F039-0002 and 7460-0250, that strongly ameliorated DSS-induced colitis. Overall, our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.
{"title":"Inhibition of METTL3 in macrophages provides protection against intestinal inflammation","authors":"Huilong Yin, Zhuan Ju, Xiang Zhang, Wenjie Zuo, Yuhang Yang, Minhua Zheng, Xiaofang Zhang, Yuning Liu, Yingran Peng, Ying Xing, Angang Yang, Rui Zhang","doi":"10.1038/s41423-024-01156-8","DOIUrl":"10.1038/s41423-024-01156-8","url":null,"abstract":"Inflammatory bowel disease (IBD) is prevalent, and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood. In this study, we discovered that increased expression of methyltransferase-like 3 (METTL3) in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate (DSS)-induced colitis. Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase (PGP), which resulted in glucose metabolism reprogramming and the suppression of CD4+ T helper 1 (Th1) cell differentiation. Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms. In addition, we developed two potent small molecule METTL3 inhibitors, namely, F039-0002 and 7460-0250, that strongly ameliorated DSS-induced colitis. Overall, our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636048","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}
γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.
γδT细胞在免疫监视中起着至关重要的作用，是先天性免疫和适应性免疫之间的桥梁。然而，人们对γδ T细胞发育和功能的代谢要求和调控仍然知之甚少。在这项研究中，我们研究了肝激酶 B1（Lkb1）在γδ T 细胞生物学中的作用，肝激酶 B1 是一种丝氨酸/苏氨酸激酶，它将细胞代谢与细胞生长和增殖联系在一起。我们的研究结果表明，Lkb1 不仅参与调节γδ T 细胞系的承诺，而且在γδ T 细胞效应功能中发挥着关键作用。具体来说，T 细胞特异性缺失 Lkb1 会导致胸腺细胞发育受损，胸腺和外周淋巴组织中的γδ T 细胞亚群发生明显改变。值得注意的是，Lkb1 的缺失抑制了 Vγ1 和 Vγ4 γδ T 细胞的承诺，促进了产生 IL-17 的 Vγ6 γδ T 细胞的成熟，并导致致命的自身免疫性肝炎（AIH）的发生。值得注意的是，清除γδT细胞或阻断IL-17可显著减轻AIH。从机理上讲，Lkb1 缺乏会破坏代谢平衡和 AMPK 活性，同时增加 mTORC1 的活化，从而导致γδ T 细胞过度活化和细胞凋亡增强。有趣的是，激活 AMPK 或抑制 mTORC1 信号传导可有效抑制 IL-17 水平并减轻 Lkb1 基因缺陷小鼠的 AIH。我们的研究结果突显了Lkb1在维持γδT细胞平衡和预防IL-17介导的自身免疫性疾病中的关键作用，为研究胸腺γδT细胞亚群确定和功能分化的代谢程序提供了新的视角。
{"title":"Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis","authors":"Zhiqiang Xiao, Shanshan Wang, Liang Luo, Wenkai Lv, Peiran Feng, Yadong Sun, Quanli Yang, Jun He, Guangchao Cao, Zhinan Yin, Meixiang Yang","doi":"10.1038/s41423-024-01163-9","DOIUrl":"10.1038/s41423-024-01163-9","url":null,"abstract":"γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624192","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 : 2024-04-17DOI: 10.1038/s41423-024-01157-7
Xiaoqing Zheng, Wen Lei, Yongmei Zhang, Han Jin, Cha Han, Fan Wu, Chonghong Jia, Ruihong Zeng, Zhanghua Chen, Yuxia Zhang, Haitao Wang, Qiang Liu, Zhi Yao, Ying Yu, Jie Zhou
Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, yet the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized by high levels of neuropilin-1 (Nrp1), termed Nrp1high monocytes. Compared with their Nrp1low counterparts, Nrp1high monocytes displayed potent immunosuppressive activity. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1high monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, by binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These findings reveal an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for treating inflammatory disorders in neonates.
新生儿的免疫系统尚未发育成熟，很容易患上炎症性疾病，如坏死性小肠结肠炎（NEC）。早期调节性免疫细胞的及时出现有助于控制新生儿的炎症，但其潜在机制仍鲜为人知。在这项研究中，我们发现了一个新生儿单核细胞亚群，其特点是神经纤蛋白-1（Nrp1）含量高，被称为 Nrp1 高单核细胞。与 Nrp1 低的单核细胞相比，Nrp1 高的单核细胞显示出强大的免疫抑制活性。髓系细胞中缺乏 Nrp1 会加重 NEC 的严重程度，而 Nrp1 高单核细胞的收养性转移则会导致 NEC 的缓解。机理研究表明，Nrp1通过与其配体Sema4a结合，诱导细胞内p38-MAPK/mTOR信号传导，并激活转录因子KLF4。KLF4 可转录 Nos2 并促进一氧化氮（NO）的产生，一氧化氮是单核细胞免疫抑制的关键介质。这些发现揭示了新生儿单核细胞中重要的免疫抑制轴，为治疗新生儿炎症性疾病提供了潜在的治疗策略。
{"title":"Neuropilin-1high monocytes protect against neonatal inflammation","authors":"Xiaoqing Zheng, Wen Lei, Yongmei Zhang, Han Jin, Cha Han, Fan Wu, Chonghong Jia, Ruihong Zeng, Zhanghua Chen, Yuxia Zhang, Haitao Wang, Qiang Liu, Zhi Yao, Ying Yu, Jie Zhou","doi":"10.1038/s41423-024-01157-7","DOIUrl":"10.1038/s41423-024-01157-7","url":null,"abstract":"Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, yet the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized by high levels of neuropilin-1 (Nrp1), termed Nrp1high monocytes. Compared with their Nrp1low counterparts, Nrp1high monocytes displayed potent immunosuppressive activity. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1high monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, by binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These findings reveal an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for treating inflammatory disorders in neonates.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615913","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 : 2024-04-17DOI: 10.1038/s41423-024-01162-w
Xiurong Wu, Zhang-Hua Yang, Yue Zheng, Jianfeng Wu, Jiahuai Han
{"title":"Bypassing PELO-mediated ATPase activation of the NLR is a common pathogenic cause of NLR-associated autoinflammatory diseases","authors":"Xiurong Wu, Zhang-Hua Yang, Yue Zheng, Jianfeng Wu, Jiahuai Han","doi":"10.1038/s41423-024-01162-w","DOIUrl":"10.1038/s41423-024-01162-w","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617939","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 : 2024-04-11DOI: 10.1038/s41423-024-01153-x
Bo Zhu, Hang Yin, Di Zhang, Meiling Zhang, Xiaojuan Chao, Luca Scimeca, Ming-Ru Wu
Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers. Despite the transformative impact of immunotherapy on cancer treatment, several outstanding challenges remain. These challenges include on-target off-tumor toxicity, systemic toxicity, and the complexity of achieving potent and sustainable therapeutic efficacy. Synthetic biology has emerged as a promising approach to overcome these obstacles, offering innovative tools for engineering living cells with customized functions. This review provides an overview of the current landscape and future prospects of cancer immunotherapy, particularly emphasizing the role of synthetic biology in augmenting its specificity, controllability, and efficacy. We delineate and discuss two principal synthetic biology strategies: those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits. This review concludes with a forward-looking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.
{"title":"Synthetic biology approaches for improving the specificity and efficacy of cancer immunotherapy","authors":"Bo Zhu, Hang Yin, Di Zhang, Meiling Zhang, Xiaojuan Chao, Luca Scimeca, Ming-Ru Wu","doi":"10.1038/s41423-024-01153-x","DOIUrl":"10.1038/s41423-024-01153-x","url":null,"abstract":"Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers. Despite the transformative impact of immunotherapy on cancer treatment, several outstanding challenges remain. These challenges include on-target off-tumor toxicity, systemic toxicity, and the complexity of achieving potent and sustainable therapeutic efficacy. Synthetic biology has emerged as a promising approach to overcome these obstacles, offering innovative tools for engineering living cells with customized functions. This review provides an overview of the current landscape and future prospects of cancer immunotherapy, particularly emphasizing the role of synthetic biology in augmenting its specificity, controllability, and efficacy. We delineate and discuss two principal synthetic biology strategies: those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits. This review concludes with a forward-looking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01153-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581774","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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