Cellular &Molecular Immunology最新文献_第8页

Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively Eomesodermin通过分别靶向KLF2和T-bet，在时空上协调NK细胞发育的早期和晚期阶段。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-05-13 DOI: 10.1038/s41423-024-01164-8

Junming He, Donglin Chen, Wei Xiong, Xinlei Hou, Yuhe Quan, Meixiang Yang, Zhongjun Dong

{"title":"Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively","authors":"Junming He, Donglin Chen, Wei Xiong, Xinlei Hou, Yuhe Quan, Meixiang Yang, Zhongjun Dong","doi":"10.1038/s41423-024-01164-8","DOIUrl":"10.1038/s41423-024-01164-8","url":null,"abstract":"Eomesodermin (Eomes) is a critical factor in the development of natural killer (NK) cells, but its precise role in temporal and spatial coordination during this process remains unclear. Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development. Specifically, the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2, another important transcription factor. ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence (CNS) of Klf2. Utilizing the CHimeric IMmune Editing (CHIME) technique, we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest. Moreover, constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency. Conversely, Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27+CD11b+ phenotype to the CD27−CD11b+ phenotype. Late-stage deficiency of Eomes led to a significant increase in T-bet expression, which subsequently increased the expression of the transcription factor Zeb2. Genetic deletion of one allele of Tbx21, encoding T-bet, effectively reversed the aberrant differentiation of Eomes-deficient NK cells. In summary, we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 7","pages":"662-673"},"PeriodicalIF":21.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916176","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}

引用次数: 0

A novel target to turn cold tumors into hot tumors: lysosomal 25-hydroxycholesterol activates AMPKα and immunosuppressive tumor-associated macrophages 将冷肿瘤变为热肿瘤的新靶点：溶酶体 25- 羟基胆固醇激活 AMPKα 和免疫抑制性肿瘤相关巨噬细胞。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-05-13 DOI: 10.1038/s41423-024-01171-9

Shuangshuang Liu, Jiaqi Wu, Xiao Tong, Li-Hao Huang

引用次数: 0

GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3 GITR通过对NLRP3的翻译后调控，加剧脓毒症中溶血磷脂酰胆碱诱导的巨噬细胞脓毒症。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-05-13 DOI: 10.1038/s41423-024-01170-w

Siping Liang, Jinyu Zhou, Can Cao, Yiting Liu, Siqi Ming, Xi Liu, Yuqi Shang, Juanfeng Lao, Qin Peng, Jiahui Yang, Minhao Wu

{"title":"GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3","authors":"Siping Liang, Jinyu Zhou, Can Cao, Yiting Liu, Siqi Ming, Xi Liu, Yuqi Shang, Juanfeng Lao, Qin Peng, Jiahui Yang, Minhao Wu","doi":"10.1038/s41423-024-01170-w","DOIUrl":"10.1038/s41423-024-01170-w","url":null,"abstract":"The NLRP3 inflammasome functions as an inflammatory driver, but its relationship with lipid metabolic changes in early sepsis remains unclear. Here, we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine (LPC) and was positively correlated with the severity of sepsis. GITR is a costimulatory molecule that is mainly expressed on T cells, but its function in macrophages is largely unknown. Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis. Furthermore, in vivo studies using either cecal ligation and puncture (CLP) or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality, while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1β deficiency attenuated sepsis severity/lethality. Mechanistically, GITR specifically enhanced inflammasome activation by regulating the posttranslational modification (PTM) of NLRP3. GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation, leading to decreasing ubiquitination but increasing acetylation of NLRP3. Overall, these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury, suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 7","pages":"674-688"},"PeriodicalIF":21.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916178","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}

引用次数: 0

Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease 中性粒细胞衍生的 PAD4 可诱导 CKMT1 的瓜氨酸化，从而加剧炎症性肠病的粘膜炎症

IF 24.1 1区医学

Cellular &Molecular Immunology Pub Date : 2024-05-08 DOI: 10.1038/s41423-024-01158-6

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

{"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":"21 6","pages":"620-633"},"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}

引用次数: 0

Distinct palmitoylation of Foxp3 regulates the function of regulatory T cells via palmitoyltransferases Foxp3的不同棕榈酰化作用通过棕榈酰转移酶调节调节性T细胞的功能

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-05-08 DOI: 10.1038/s41423-024-01166-6

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

引用次数: 0

Immunopeptidome mining reveals a novel ERS-induced target in T1D 免疫肽组挖掘揭示 T1D 中 ERS 诱导的新靶点

IF 24.1 1区医学

Cellular &Molecular Immunology Pub Date : 2024-04-30 DOI: 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

{"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":"21 6","pages":"604-619"},"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}

引用次数: 0

Tissue-specific features of innate lymphoid cells in antiviral defense 先天性淋巴细胞在抗病毒防御中的组织特异性特征

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-04-29 DOI: 10.1038/s41423-024-01161-x

Sytse J. Piersma

引用次数: 0

Inhibition of METTL3 in macrophages provides protection against intestinal inflammation 抑制巨噬细胞中的 METTL3 可防止肠道炎症

IF 24.1 1区医学

Cellular &Molecular Immunology Pub Date : 2024-04-22 DOI: 10.1038/s41423-024-01156-8

Huilong Yin, Zhuan Ju, Xiang Zhang, Wenjie Zuo, Yuhang Yang, Minhua Zheng, Xiaofang Zhang, Yuning Liu, Yingran Peng, Ying Xing, Angang Yang, Rui Zhang

{"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":"21 6","pages":"589-603"},"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}

引用次数: 0

Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis Lkb1 协调γδ T 细胞的代谢和功能，控制 IL-17 介导的自身免疫性肝炎

IF 24.1 1区医学

Cellular &Molecular Immunology Pub Date : 2024-04-19 DOI: 10.1038/s41423-024-01163-9

Zhiqiang Xiao, Shanshan Wang, Liang Luo, Wenkai Lv, Peiran Feng, Yadong Sun, Quanli Yang, Jun He, Guangchao Cao, Zhinan Yin, Meixiang Yang

{"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":"21 6","pages":"546-560"},"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}

引用次数: 0

Targeting macrophage metabolism to enhance tumor immunotherapy 以巨噬细胞代谢为靶点加强肿瘤免疫疗法

IF 24.1 1区医学

Cellular &Molecular Immunology Pub Date : 2024-04-17 DOI: 10.1038/s41423-024-01149-7

Jing Liu, Zhibo Ma, Wenlong Jia, Peixiang Lan

引用次数: 0