EMBO Molecular Medicine最新文献_第7页

Boosting human immunology: harnessing the potential of immune organoids. 增强人体免疫学：利用免疫类器官的潜力。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-01-27 DOI: 10.1038/s44321-025-00193-8

Maximilian Moll, Dirk Baumjohann

{"title":"Boosting human immunology: harnessing the potential of immune organoids.","authors":"Maximilian Moll, Dirk Baumjohann","doi":"10.1038/s44321-025-00193-8","DOIUrl":"10.1038/s44321-025-00193-8","url":null,"abstract":"Studying the human immune system in vivo is challenging and often not possible. Therefore, most human immunology studies have been predominantly confined to peripheral blood analyses, which by themselves have inherent limitations, as many immune reactions take place within tissues. For example, potent antibody responses that contribute to fighting infections and provide protection following vaccination require cellular interactions between B cells and T cells in specialized micro-anatomical structures called germinal centers, which are found in secondary lymphoid organs such as spleen, lymph nodes, and tonsils. Thus, there is a clear demand for novel enhanced experimental systems that faithfully recapitulate the intricate dynamics of the human immune system as much as possible. In this review, we discuss recent advances in versatile human tonsil/adenoid tissue-based ex vivo immune organoid cultures as well as related cancer and autoimmunity-focused experimental setups. These systems have been implemented as translational immunology platforms for in-depth analyses of human B and T cell-mediated immune responses, thereby facilitating mechanistic studies as well as drug and vaccine testing in a human-first approach.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"385-394"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052071","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}

引用次数: 0

An AI-assisted morphoproteomic approach is a supportive tool in esophagitis-related precision medicine. 人工智能辅助的形态蛋白质组学方法是食管炎相关精准医学的支持工具。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-02-03 DOI: 10.1038/s44321-025-00194-7

Sven Mattern, Vanessa Hollfoth, Eyyub Bag, Arslan Ali, Philip Riemenschneider, Mohamed A Jarboui, Karsten Boldt, Mihaly Sulyok, Anabel Dickemann, Julia Luibrand, Stefano Fusco, Mirita Franz-Wachtel, Kerstin Singer, Benjamin Goeppert, Oliver Schilling, Nisar Malek, Falko Fend, Boris Macek, Marius Ueffing, Stephan Singer

{"title":"An AI-assisted morphoproteomic approach is a supportive tool in esophagitis-related precision medicine.","authors":"Sven Mattern, Vanessa Hollfoth, Eyyub Bag, Arslan Ali, Philip Riemenschneider, Mohamed A Jarboui, Karsten Boldt, Mihaly Sulyok, Anabel Dickemann, Julia Luibrand, Stefano Fusco, Mirita Franz-Wachtel, Kerstin Singer, Benjamin Goeppert, Oliver Schilling, Nisar Malek, Falko Fend, Boris Macek, Marius Ueffing, Stephan Singer","doi":"10.1038/s44321-025-00194-7","DOIUrl":"10.1038/s44321-025-00194-7","url":null,"abstract":"Esophagitis is a frequent, but at the molecular level poorly characterized condition with diverse underlying etiologies and treatments. Correct diagnosis can be challenging due to partially overlapping histological features. By proteomic profiling of routine diagnostic FFPE biopsy specimens (n = 55) representing controls, Reflux- (GERD), Eosinophilic-(EoE), Crohn's-(CD), Herpes simplex (HSV) and Candida (CA)-esophagitis by LC-MS/MS (DIA), we identified distinct signatures and functional networks (e.g. mitochondrial translation (EoE), immunoproteasome, complement and coagulations system (CD), ribosomal biogenesis (GERD)), and pathogen-specific proteins for HSV and CA. Moreover, combining these signatures with histological parameters in a machine learning model achieved high diagnostic accuracy (100% training set, 93.8% test set), and supported diagnostic decisions in borderline/challenging cases. Applied to a young patient representing a use case, the external GERD diagnosis could be revised to CD and ICAM1 was identified as highly abundant therapeutic target. This resulted in CyclosporinA as a personalized treatment recommendation by the local multidisciplinary molecular inflammation board. Our integrated AI-assisted morphoproteomic approach allows deeper insights in disease-specific molecular alterations and represents a promising tool in esophagitis-related precision medicine.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"441-468"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122538","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}

引用次数: 0

Repression of apelin Furin cleavage sites provides antimetastatic strategy in colorectal cancer. 抑制apelin Furin切割位点提供了抗结直肠癌转移的策略。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1038/s44321-025-00196-5

Béatrice Demoures, Fabienne Soulet, Jean Descarpentrie, Isabel Galeano-Otero, José Sanchez Collado, Maria Casado, Tarik Smani, Alvaro González, Isabel Alves, Fabrice Lalloué, Bernard Masri, Estelle Rascol, Jean-William Dupuy, Cyril Dourthe, Frédéric Saltel, Anne-Aurélie Raymond, Iker Badiola, Serge Evrard, Bruno Villoutreix, Simon Pernot, Géraldine Siegfried, Abdel-Majid Khatib

{"title":"Repression of apelin Furin cleavage sites provides antimetastatic strategy in colorectal cancer.","authors":"Béatrice Demoures, Fabienne Soulet, Jean Descarpentrie, Isabel Galeano-Otero, José Sanchez Collado, Maria Casado, Tarik Smani, Alvaro González, Isabel Alves, Fabrice Lalloué, Bernard Masri, Estelle Rascol, Jean-William Dupuy, Cyril Dourthe, Frédéric Saltel, Anne-Aurélie Raymond, Iker Badiola, Serge Evrard, Bruno Villoutreix, Simon Pernot, Géraldine Siegfried, Abdel-Majid Khatib","doi":"10.1038/s44321-025-00196-5","DOIUrl":"10.1038/s44321-025-00196-5","url":null,"abstract":"The adipokine apelin has been directly implicated in various physiological processes during embryogenesis and human cancers. Nevertheless, the importance of the conversion of its precursor proapelin to mature apelin in tumorigenesis remains unknown. In this study, we identify Furin as the cellular proprotein convertase responsible for proapelin cleavage. We explore the therapeutic potential of targeting proapelin cleavage sites in metastatic colorectal cancer by introducing apelin-dm, a modified variant resulting from alteration in proapelin cleavage sites. Apelin-dm demonstrates efficacy in inhibiting tumor growth, promoting cell death, suppressing angiogenesis, and early colorectal liver metastasis events. Proteomic analysis reveals reciprocal regulation between apelin and apelin-dm on proteins associated with clinical outcomes in colon cancer patients. Apelin-dm emerges as a modulator of apelin receptor dynamics, influencing affinity, internalization, and repression of apelin signaling linked to various protein kinases. Pharmacokinetic and toxicity assessments confirm the specificity, safety, and stability of apelin-dm, as well as its facile hepatic metabolism. These findings position targeting proapelin cleavage as a promising therapeutic strategy against metastatic colorectal cancer, paving the way for further clinical exploration.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"504-534"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440089","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}

引用次数: 0

Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease. 女性在阿尔茨海默病中与strem - 2和CSF p-tau之间有更强的联系。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-10 DOI: 10.1038/s44321-024-00190-3

Davina Biel, Marc Suárez-Calvet, Anna Dewenter, Anna Steward, Sebastian N Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier

{"title":"Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease.","authors":"Davina Biel, Marc Suárez-Calvet, Anna Dewenter, Anna Steward, Sebastian N Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier","doi":"10.1038/s44321-024-00190-3","DOIUrl":"10.1038/s44321-024-00190-3","url":null,"abstract":"In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau181. To determine effects of microglial activation on p-tau181, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau181 levels. Higher sTREM2 was associated with elevated p-tau181, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau181 levels and faster p-tau181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"235-248"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964253","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}

引用次数: 0

Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors. 表达MATEs的溶瘤病毒促进肿瘤中不依赖靶标的t细胞活化。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-09 DOI: 10.1038/s44321-024-00187-y

Malin Peter, Bettina Mundt, Arne Menze, Norman Woller, Valery Volk, Amanda M Ernst, Leon A Öhler, Steven R Talbot, Heiner Wedemeyer, Christine Falk, Friedrich Feuerhake, Thomas C Wirth, Florian Kühnel

{"title":"Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors.","authors":"Malin Peter, Bettina Mundt, Arne Menze, Norman Woller, Valery Volk, Amanda M Ernst, Leon A Öhler, Steven R Talbot, Heiner Wedemeyer, Christine Falk, Friedrich Feuerhake, Thomas C Wirth, Florian Kühnel","doi":"10.1038/s44321-024-00187-y","DOIUrl":"10.1038/s44321-024-00187-y","url":null,"abstract":"Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T cells and improved killing of MC38 colon carcinoma cells. Similarly, humanized MATEs activated T cells in PBMCs from human donors. In MC38-tumors in mice, MATE-expression by the oncolytic adenovirus Ad5/11 facilitated intratumoral T-cell activation, reduced tumor growth and prolonged survival accompanied by infiltration of tumor-directed CD8+ T cells and improved CD8/CD4 T-cell ratio. Absence of early T-cell activation in tumor draining lymph nodes suggests the safe applicability of this strategy. Furthermore, MATE-expression by Ad5/11 was capable of breaking resistance to αPD-1 checkpoint therapy thereby promoting T-cell/tumor cell proximity and clustering of CD8+ and CD4+ T cells. In summary, we demonstrated that MATE expressing OVs are powerful T-cell activating tools suitable for local immunotherapy of a broad range of tumors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"265-300"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946571","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}

引用次数: 0

PlexinD1 is a driver and a therapeutic target in advanced prostate cancer. PlexinD1是晚期前列腺癌的驱动因子和治疗靶点。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44321-024-00186-z

Jing Wei, Jing Wang, Wen Guan, Jingjing Li, Tianjie Pu, Eva Corey, Tzu-Ping Lin, Allen C Gao, Boyang Jason Wu

{"title":"PlexinD1 is a driver and a therapeutic target in advanced prostate cancer.","authors":"Jing Wei, Jing Wang, Wen Guan, Jingjing Li, Tianjie Pu, Eva Corey, Tzu-Ping Lin, Allen C Gao, Boyang Jason Wu","doi":"10.1038/s44321-024-00186-z","DOIUrl":"10.1038/s44321-024-00186-z","url":null,"abstract":"Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes. PlexinD1 critically maintains CRPC aggressive behaviors in vitro and in vivo, and confers stemness and cellular plasticity to promote multilineage differentiation including a neuroendocrine-like phenotype for ARSI resistance. Mechanistically, PlexinD1 is upregulated upon relief of AR-mediated transcriptional repression of PlexinD1 under ARSI treatment, and subsdquently transactivates ErbB3 and cMet via direct interaction, which triggers the ERK/AKT pathways to induce noncanonical Gli1-dictated Hedgehog signaling, facilitating the growth and plasticity of PCa cells. Blockade of PlexinD1 by the protein inhibitor D1SP restricted CRPC growth in multiple preclinical models. Collectively, these findings characterize PlexinD1's contribution to PCa progression and offer a potential PlexinD1-targeted therapy for advanced PCa.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"336-364"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920817","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}

引用次数: 0

CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts. CAR - t细胞相关的继发性恶性肿瘤挑战了当前的药物警戒概念。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1038/s44321-024-00183-2

Philipp Berg, Gabriele Ruppert-Seipp, Susanne Müller, Gabriele D Maurer, Jessica Hartmann, Udo Holtick, Christian J Buchholz, Markus B Funk

{"title":"CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts.","authors":"Philipp Berg, Gabriele Ruppert-Seipp, Susanne Müller, Gabriele D Maurer, Jessica Hartmann, Udo Holtick, Christian J Buchholz, Markus B Funk","doi":"10.1038/s44321-024-00183-2","DOIUrl":"10.1038/s44321-024-00183-2","url":null,"abstract":"Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This is of particular relevance for gene therapy products that integrate into the host genome. We present a summary of case reports related to different CAR T products and the rationale for case causality assessment. In this context, possible pathophysiologic mechanisms and differences between CAR T products to be taken into account are discussed. The unparalleled complexity of the case follow-up and the multistep process of cancer development necessitates a case-by-case consideration. This highlights challenges in the pharmacovigilance of advanced therapy medicinal products and underlines the importance of testing for vector presence, integration location and gene expression profile for an informed case assessment of suspected secondary malignancies with the aim to obtain a better understanding of contributing factors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"17 2","pages":"211-218"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406504","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}

引用次数: 0

A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors. 新抗原特异性TCR-T细胞治疗HLA-A*2402阳性实体瘤的治疗方案

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44321-024-00184-1

Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li

{"title":"A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors.","authors":"Yuncheng Bei, Ying Huang, Nandie Wu, Yishan Li, Ruihan Xu, Baorui Liu, Rutian Li","doi":"10.1038/s44321-024-00184-1","DOIUrl":"10.1038/s44321-024-00184-1","url":null,"abstract":"The adoptive transfer of TCR-T cells specific to neoantigens preferentially exhibits potent cytotoxicity to tumor cells and has shown promising efficacy in various preclinical human cancers. In this study, we first identified a functional TCR, Tcr-1, which selectively recognized the SYT-SSX fusion neoantigen shared by most synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) demonstrated HLA-A*2402-restricted, antigen-specific anti-tumoral efficacy against synovial sarcoma cells, both in vitro and in vivo. Furthermore, to extend its application, we developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into stimuli-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (Neo-AgNPs) for tumor targeting delivery. As expected, Neo-AgNPs were proven to have great tumor penetration and local release. In situ, the modification was able to direct engineered Tcr-T1 against other HLA-A*2402-positive malignant cancer cell lines with significant antigen-specific cytotoxicity despite their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has great potential for further clinical investigation and provides new insight for future TCR-T cell therapy development.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"365-383"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920815","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}

引用次数: 0

Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors. 微生物代谢物调节杏仁核神经元的过度兴奋性和焦虑相关行为。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-02-05 DOI: 10.1038/s44321-024-00179-y

Weonjin Yu, Yixin Xiao, Anusha Jayaraman, Yi-Chun Yen, Hae Ung Lee, Sven Pettersson, H Shawn Je

{"title":"Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors.","authors":"Weonjin Yu, Yixin Xiao, Anusha Jayaraman, Yi-Chun Yen, Hae Ung Lee, Sven Pettersson, H Shawn Je","doi":"10.1038/s44321-024-00179-y","DOIUrl":"10.1038/s44321-024-00179-y","url":null,"abstract":"Changes in gut microbiota composition have been linked to anxiety behavior in rodents. However, the underlying neural circuitry linking microbiota and their metabolites to anxiety behavior remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed to live microbes, increased anxiety-related behavior was observed correlating with a significant increase in the immediate early c-Fos gene in the basolateral amygdala (BLA). This phenomenon coincided with increased intrinsic excitability and spontaneous synaptic activity of BLA pyramidal neurons associated with reduced small conductance calcium-activated potassium (SK) channel currents. Importantly, colonizing GF mice to live microbes or the microbial-derived metabolite indoles reverted SK channel activities in BLA pyramidal neurons and reduced the anxiety behavioral phenotype. These results are consistent with a molecular mechanism by which microbes and or microbial-derived indoles, regulate functional changes in the BLA neurons. Moreover, this microbe metabolite regulation of anxiety links these results to ancient evolutionarily conserved defense mechanisms associated with anxiety-related behaviors in mammals.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"249-264"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11821874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255148","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}

引用次数: 0

Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation. 巨噬细胞诱导的肠道神经变性导致肠道炎症期间的运动障碍。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1038/s44321-024-00189-w

Mona Breßer, Kevin D Siemens, Linda Schneider, Jonah E Lunnebach, Patrick Leven, Tim R Glowka, Kristin Oberländer, Elena De Domenico, Joachim L Schultze, Joachim Schmidt, Jörg C Kalff, Anja Schneider, Sven Wehner, Reiner Schneider

{"title":"Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation.","authors":"Mona Breßer, Kevin D Siemens, Linda Schneider, Jonah E Lunnebach, Patrick Leven, Tim R Glowka, Kristin Oberländer, Elena De Domenico, Joachim L Schultze, Joachim Schmidt, Jörg C Kalff, Anja Schneider, Sven Wehner, Reiner Schneider","doi":"10.1038/s44321-024-00189-w","DOIUrl":"10.1038/s44321-024-00189-w","url":null,"abstract":"Current studies pictured the enteric nervous system and macrophages as modulators of neuroimmune processes in the inflamed gut. Expanding this view, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. In the early postsurgical phase, we detected strong neuronal activation, followed by transcriptional and translational signatures indicating neuronal death and synaptic damage. Simultaneously, our study revealed neurodegenerative profiles in macrophage-specific transcriptomes after postoperative trauma. Validating the role of resident and monocyte-derived macrophages, we depleted macrophages by CSF-1R-antibodies and used CCR2-/- mice, known for reduced monocyte infiltration, in POI studies. Only CSF-1R-antibody-treated animals showed decreased neuronal death and lessened synaptic decay, emphasizing the significance of resident macrophages. In human gut samples taken early and late during abdominal surgery, we substantiated the mouse model data and found reactive and apoptotic neurons and dysregulation in synaptic genes, indicating a species' overarching mechanism. Our study demonstrates that surgical trauma activates enteric neurons and induces neurodegeneration, mediated by resident macrophages, introducing neuroprotection as an option for faster recovery after surgery.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"17 2","pages":"301-335"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406508","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}

引用次数: 0