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Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males. 线粒体伴侣TRAP1的突变导致自闭症,且男性症状更为严重。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-27 DOI: 10.1038/s44321-024-00147-6
Małgorzata Rydzanicz,Bozena Kuzniewska,Marta Magnowska,Tomasz Wójtowicz,Aleksandra Stawikowska,Anna Hojka,Ewa Borsuk,Ksenia Meyza,Olga Gewartowska,Jakub Gruchota,Jacek Miłek,Patrycja Wardaszka,Izabela Chojnicka,Ludwika Kondrakiewicz,Dorota Dymkowska,Alicja Puścian,Ewelina Knapska,Andrzej Dziembowski,Rafał Płoski,Magdalena Dziembowska
There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.
越来越多的证据表明,自闭症谱系障碍(ASD)中存在线粒体功能障碍,但其中的因果关系尚不清楚。在一名同卵双胞胎未受影响的 ASD 患者身上,我们发现了 TRAP1 基因中的一个后染色体镶嵌突变 p.Q639*,该基因编码 HSP90 家族的线粒体伴侣蛋白。对176名无亲属关系的ASD疑似患者进行的额外筛查发现,一名男性患者的TRAP1基因变异与之完全相同,该患者的母亲是健康人。值得注意的是,新产生的基因敲入 Trap1 p.Q641* 小鼠表现出与 ASD 相关的行为异常,雄性小鼠比雌性小鼠更明显。相应地,Trap1 p.Q641*突变也导致了突触可塑性、突触前线粒体数量和线粒体呼吸的性别特异性变化。因此,TRAP1 p.Q639*突变是首个因线粒体蛋白平衡受损而导致单基因自闭症的实例。
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引用次数: 0
RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity. RIG-I 是限制 CD8+ T 细胞抗肿瘤免疫的细胞内检查点。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-25 DOI: 10.1038/s44321-024-00136-9
Xiaobing Duan,Jiali Hu,Yuncong Zhang,Xiaoguang Zhao,Mingqi Yang,Taoping Sun,Siya Liu,Xin Chen,Juan Feng,Wenting Li,Ze Yang,Yitian Zhang,Xiaowen Lin,Dingjie Liu,Ya Meng,Guang Yang,Qiuping Lin,Guihai Zhang,Haihong Lei,Zhengsheng Yi,Yanyan Liu,Xiaobing Liang,Yujuan Wu,Wenqing Diao,Zesong Li,Haihai Liang,Meixiao Zhan,Hong-Wei Sun,Xian-Yang Li,Ligong Lu
Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.
视黄酸诱导基因 I(RIG-I)是一种参与先天性免疫的模式识别受体,但它在适应性免疫,特别是在 CD8+ T 细胞抗肿瘤免疫中的作用仍不清楚。在这里,我们证明了 RIG-I 在肿瘤浸润的 CD8+ T 细胞中上调,它作为细胞内检查点负调控 CD8+ T 细胞功能并限制抗肿瘤免疫。从机理上讲,RIG-I 在 CD8+ T 细胞中的上调是由活化的 T 细胞诱导的,并直接抑制 AKT/糖酵解信号通路。此外,敲除 RIG-I 可增强被收养转移 T 细胞对实体瘤的疗效,抑制 RIG-I 可增强对 PD-1 阻断的反应。总之,我们的研究发现 RIG-I 是一种细胞内检查点,也是在癌症免疫疗法中缓解 T 细胞抑制性限制的潜在靶点,可以单独使用,也可以与免疫检查点抑制剂联合使用。
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引用次数: 0
Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types. 出版商更正:针对多种癌症类型的 LGR5 新型免疫疗法。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-25 DOI: 10.1038/s44321-024-00139-6
Hung-Chang Chen,Nico Mueller,Katherine Stott,Chrysa Kapeni,Eilidh Rivers,Carolin M Sauer,Flavio Beke,Stephen J Walsh,Nicola Ashman,Louise O'Brien,Amir Rafati Fard,Arman Ghodsinia,Changtai Li,Fadwa Joud,Olivier Giger,Inti Zlobec,Ioana Olan,Sarah J Aitken,Matthew Hoare,Richard Mair,Eva Serrao,James D Brenton,Alicia Garcia-Gimenez,Simon E Richardson,Brian Huntly,David R Spring,Mikkel-Ole Skjoedt,Karsten Skjødt,Marc de la Roche,Maike de la Roche
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引用次数: 0
Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway. 神经前体细胞通过激活干扰素γ途径挽救雷特综合征的症状。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-20 DOI: 10.1038/s44321-024-00144-9
Angelisa Frasca, Federica Miramondi, Erica Butti, Marzia Indrigo, Maria Balbontin Arenas, Francesca M Postogna, Arianna Piffer, Francesco Bedogni, Lara Pizzamiglio, Clara Cambria, Ugo Borello, Flavia Antonucci, Gianvito Martino, Nicoletta Landsberger

The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analyzed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT.

神经前体细胞(NPC)移植对多种神经系统疾病的有益作用已得到证实,这些作用通常由免疫调节和神经营养分子的分泌介导。因此,我们研究了雷特综合征(Rett Syndrome,RTT)是否能从基于神经干细胞的治疗中获益。通过体外联合培养,我们证明了通过感知病理环境,NPC 分泌的因子可诱导 Mecp2 缺陷神经元典型的形态和突触缺陷的恢复。在体内,我们证明在 RTT 小鼠脑内移植 NPC 能显著改善神经功能。为了揭示介导益处效应的分子机制,我们分析了移植动物小脑的转录谱,发现干扰素γ(IFNγ)通路可能参与其中。因此,我们报告了 IFNγ 在 Mecp2 缺陷模型中挽救突触缺陷以及运动和认知改变的能力,从而表明这一分子途径是 RTT 的潜在治疗靶点。
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引用次数: 0
Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease. 多组学揭示微生物代谢物是克罗恩病肠纤维化的关键因素。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00129-8
Xuehua Li,Shixian Hu,Xiaodi Shen,Ruonan Zhang,Caiguang Liu,Lin Xiao,Jinjiang Lin,Li Huang,Weitao He,Xinyue Wang,Lili Huang,Qingzhu Zheng,Luyao Wu,Canhui Sun,Zhenpeng Peng,Minhu Chen,Ziping Li,Rui Feng,Yijun Zhu,Yangdi Wang,Zhoulei Li,Ren Mao,Shi-Ting Feng
Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.
肠纤维化是克罗恩病(CD)患者致残的主要原因,但目前尚缺乏有效的治疗策略。在此,我们报告了对278名克罗恩病患者和28名健康对照者的肠道微生物群和粪便/血液代谢物进行的多组学分析,发现了中重度肠纤维化患者肠道微生物群(如Lachnospiraceae、Ruminococcaceae、Muribaculaceae、Saccharimonadales)和代谢物(如L-天冬氨酸、谷氨酰胺、乙基甲基乙酸)的特征性改变。通过整合多组学数据与磁共振肠造影特征,建立了微生物代谢物与肠纤维化相关形态学改变之间的潜在联系。这些潜在联系由氨基酸(如 L-天门冬氨酸)、初级胆汁酸和谷氨酰胺的特定组合介导。最后,我们提供了 L-天门冬氨酸在体外和体内加重肠纤维化的因果证据。总之,我们为肠道微生物群及其代谢产物促进 CD 肠道纤维化的假说提供了生物学上合理的解释,同时也为治疗试验确定了潜在的靶点。
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引用次数: 0
ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer. 抑制 ERK5 可克服突变 KRAS 驱动的非小细胞肺癌对 FAK 抑制剂的耐药性。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00138-7
Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou
Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.
在 30% 的非小细胞肺癌(NSCLC)中,突变的 KRAS 是致癌驱动因素,并与转移性和耐药性肿瘤有关。病灶粘附激酶(FAK)是维持KRAS驱动的肺部肿瘤的介质,尽管FAK抑制剂目前正在临床开发中,但临床数据表明它们在产生长期抗肿瘤反应方面的功效有限。在这里,我们揭示了两种FAK相互作用因子,即细胞外信号调节激酶5(ERK5)和细胞周期蛋白依赖性激酶5(CDK5),它们是FAK介导的维持KRAS突变型NSCLC的关键因素。抑制ERK5和CDK5可协同抑制FAK功能,减少增殖,并因ROS诱导的DNA损伤加剧而诱导细胞凋亡。因此,在 KrasG12D 驱动的肺腺癌小鼠模型中,同时药物抑制 ERK5 和 CDK5 可抑制肿瘤进展并促进癌细胞死亡。对FAK抑制剂具有抗药性的癌细胞显示出增强的ERK5-FAK信号抑制DNA损伤。值得注意的是,ERK5抑制能阻止FAK抑制剂耐药性的产生,显著提高抗肿瘤反应的疗效。因此,我们建议将ERK5抑制作为一种潜在的联合靶向策略,以对抗NSCLC中的FAK抑制剂耐药性。
{"title":"ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer.","authors":"Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou","doi":"10.1038/s44321-024-00138-7","DOIUrl":"https://doi.org/10.1038/s44321-024-00138-7","url":null,"abstract":"Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233519","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
An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress. 新陈代谢调整的内在机制促进了心脏对压力的恢复能力。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00132-z
Matteo Sorge,Giulia Savoré,Andrea Gallo,Davide Acquarone,Mauro Sbroggiò,Silvia Velasco,Federica Zamporlini,Saveria Femminò,Enrico Moiso,Giampaolo Morciano,Elisa Balmas,Andrea Raimondi,Gabrielle Nattenberg,Rachele Stefania,Carlo Tacchetti,Angela Maria Rizzo,Paola Corsetto,Alessandra Ghigo,Emilia Turco,Fiorella Altruda,Lorenzo Silengo,Paolo Pinton,Nadia Raffaelli,Nathan J Sniadecki,Claudia Penna,Pasquale Pagliaro,Emilio Hirsch,Chiara Riganti,Guido Tarone,Alessandro Bertero,Mara Brancaccio
Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.
要找到保护心脏的有效方法,确定心脏复原力的分子机制至关重要。心脏通过脂肪酸氧化产生生理水平的 ROS,但应激事件会增加 ROS,导致线粒体功能障碍和心脏功能损伤。Melusin 是一种肌肉特异性伴侣蛋白,在应激过程中对心肌代偿性重塑是必需的。我们在此报告了 Melusin 在线粒体中的定位,它与线粒体三功能蛋白(脂肪酸氧化的关键酶)结合并降低其活性。通过研究小鼠和人类诱导多能干细胞衍生的心肌细胞,我们发现 Melusin 可减少心肌中的脂质氧化,并在稳态、压力过载和多柔比星治疗期间限制 ROS 的产生,从而防止线粒体功能障碍。因此,在压力刺激下同时使用脂质氧化抑制剂曲美他嗪治疗可限制 ROS 的积累,防止长期心脏功能障碍。这些发现揭示了心脏代谢调节的生理机制,并证明及时限制脂质代谢是提高心脏抗应激能力的一种潜在治疗策略。
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引用次数: 0
CRISPR-enabled point-of-care genotyping for APOL1 genetic risk assessment. 用于 APOL1 遗传风险评估的 CRISPR 支持的护理点基因分型。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00126-x
Robert Greensmith,Isadora T Lape,Cristian V Riella,Alexander J Schubert,Jakob J Metzger,Anand S Dighe,Xiao Tan,Bernhard Hemmer,Josefine Rau,Sarah Wendlinger,Nora Diederich,Anja Schütz,Leonardo V Riella,Michael M Kaminski
Detecting genetic variants enables risk factor identification, disease screening, and initiation of preventative therapeutics. However, current methods, relying on hybridization or sequencing, are unsuitable for point-of-care settings. In contrast, CRISPR-based-diagnostics offer high sensitivity and specificity for point-of-care applications. While these methods have predominantly been used for pathogen sensing, their utilization for genotyping is limited. Here, we report a multiplexed CRISPR-based genotyping assay using LwaCas13a, PsmCas13b, and LbaCas12a, enabling the simultaneous detection of six genotypes. We applied this assay to identify genetic variants in the APOL1 gene prevalent among African Americans, which are associated with an 8-30-fold increase in the risk of developing kidney disease. Machine learning facilitated robust analysis across a multicenter clinical cohort of more than 100 patients, accurately identifying their genotypes. In addition, we optimized the readout using a multi-analyte lateral-flow assay demonstrating the ability for simplified genotype determination of clinical samples. Our CRISPR-based genotyping assay enables cost-effective point-of-care genetic variant detection due to its simplicity, versatility, and fast readout.
检测基因变异有助于识别风险因素、筛查疾病和启动预防性疗法。然而,目前依赖杂交或测序的方法并不适合在护理点环境中使用。相比之下,基于 CRISPR 的诊断方法具有高灵敏度和高特异性,可用于护理点应用。虽然这些方法主要用于病原体检测,但在基因分型方面的应用却很有限。在此,我们报告了一种基于 CRISPR 的多重基因分型检测方法,该方法使用 LwaCas13a、PsmCas13b 和 LbaCas12a,可同时检测六种基因型。我们应用这种检测方法鉴定了非裔美国人中普遍存在的 APOL1 基因中的遗传变异,这些变异与肾病患病风险增加 8-30 倍有关。机器学习有助于对 100 多名患者的多中心临床队列进行稳健分析,准确确定他们的基因型。此外,我们还利用多分析横向流动测定法优化了读出结果,证明了简化临床样本基因型测定的能力。我们基于CRISPR的基因分型测定因其简便性、多功能性和快速读出,实现了具有成本效益的床旁基因变异检测。
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引用次数: 0
A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death. HNF4α在多微生物败血症相关代谢重编程和死亡中的关键作用
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-11 DOI: 10.1038/s44321-024-00130-1
Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert
In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.
在败血症中,有限的食物摄入量和增加的能量消耗会诱发饥饿反应,而肝脏 PPARα 表达的快速下降会损害这种反应,PPARα 是细胞内游离脂肪酸分解过程中必不可少的转录因子。PPARα 下调的上游机制尚不清楚。我们发现脓毒症会导致肝脏 HNF4α 逐渐丧失功能,而 HNF4α 对包括 PPARα 在内的几种重要核受体的表达有很大影响。肝细胞中 HNF4α 的耗竭会显著增加败血症致死率、脂肪变性和器官损伤,并阻止对 IL6 的充分反应,而 IL6 对肝脏再生和存活至关重要。HNF4α激动剂能在所有水平上防止败血症,而与细菌负荷无关,这表明HNF4α对败血症的耐受性至关重要。总之,脓毒症期间肝脏 HNF4α 活性降低,导致 PPARα 下调、代谢问题和 IL6 介导的急性期反应紊乱。这些发现为脓毒症提供了新的见解和治疗方案。
{"title":"A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.","authors":"Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert","doi":"10.1038/s44321-024-00130-1","DOIUrl":"https://doi.org/10.1038/s44321-024-00130-1","url":null,"abstract":"In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"10 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174785","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
Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice. 婴儿期肠簇细胞的免疫训练可增强小鼠宿主对肠道病毒感染的防御能力。
IF 11.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-11 DOI: 10.1038/s44321-024-00128-9
Deyan Chen,Jing Wu,Fang Zhang,Ruining Lyu,Qiao You,Yajie Qian,Yurong Cai,Xiaoyan Tian,Hongji Tao,Yating He,Waqas Nawaz,Zhiwei Wu
Innate immune cells have been acknowledged as trainable in recent years. While intestinal tuft cells are recognized for their crucial roles in the host defense against intestinal pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), a prevalent enterovirus that primarily infects children but rarely infects adults. At present, there is a significant expansion of intestinal tuft cells in the EV71-infected mouse model, which is associated with EV71-induced interleukin-25 (IL-25) production. Further, we found that IL-25 pre-treatment at 2 weeks old mouse enabled tuft cells to acquire immune memory. This was evidenced by the rapid expansion and stronger response of IL-25-trained tuft cells in response to EV71 infection at 6 weeks old, surpassing the reactivity of naïve tuft cells in mice without IL-25-trained progress. Interestingly, IL-25-trained intestinal tuft cells exhibit anti-enteroviral effect via producing a higher level of IL-25. Mechanically, IL-25 treatment upregulates spermidine/spermine acetyl-transferase enzyme (SAT1) expression, mediates intracellular polyamine deficiency, further inhibits enterovirus replication. In summary, tuft cells can be trained by IL-25, which supports faster and higher level IL-25 production in response to EV71 infection and further exhibits anti-enteroviral effect via SAT1-mediated intracellular polyamine deficiency. Given that IL-25 can be induced by multiple gut microbes during human growth and development, including shifts in gut flora abundance, which may partially explain the different susceptibility to enteroviral infections between adults and children.
近年来,先天性免疫细胞被认为是可以训练的。虽然肠套叠细胞在宿主防御肠道病原体的过程中发挥着至关重要的作用,但其可训练性仍存在不确定性。肠道病毒 71(EV71)是一种流行的肠道病毒,主要感染儿童,但很少感染成人。目前,在 EV71 感染的小鼠模型中,肠绒毛细胞显著扩张,这与 EV71 诱导的白细胞介素-25(IL-25)分泌有关。此外,我们还发现,在小鼠2周大时进行IL-25预处理可使肠套叠细胞获得免疫记忆。经过IL-25训练的簇细胞在6周大时对EV71感染的反应迅速扩大且反应更强,超过了没有经过IL-25训练的小鼠幼稚簇细胞的反应性,这就是证明。有趣的是,经过IL-25训练的肠绒毛细胞通过产生更高水平的IL-25表现出抗肠病毒作用。从机理上讲,IL-25处理可上调精胺/精胺乙酰转移酶(SAT1)的表达,介导细胞内多胺的缺乏,进一步抑制肠道病毒的复制。总之,IL-25可训练丛细胞,使其在应对EV71感染时产生更快、更高水平的IL-25,并通过SAT1介导的细胞内多胺缺乏进一步发挥抗肠病毒作用。鉴于IL-25可在人体生长发育过程中由多种肠道微生物诱导,包括肠道菌群丰度的变化,这可能部分解释了成人和儿童对肠道病毒感染的易感性不同。
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引用次数: 0
期刊
EMBO Molecular Medicine
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