ImmunityPub Date : 2025-06-05DOI: 10.1016/j.immuni.2025.05.001
Jesse Garcia Castillo, Sebastian Fernandez, Timothy Campbell, Diego Gonzalez Ventura, Jacob Williams, Julia Ybarra, Nicole Flores Hernandez, Elina Wells, Daniel A. Portnoy, Michel DuPage
{"title":"Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy","authors":"Jesse Garcia Castillo, Sebastian Fernandez, Timothy Campbell, Diego Gonzalez Ventura, Jacob Williams, Julia Ybarra, Nicole Flores Hernandez, Elina Wells, Daniel A. Portnoy, Michel DuPage","doi":"10.1016/j.immuni.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.001","url":null,"abstract":"Bacteria engineered to express tumor antigens as cancer vaccines have produced mixed results. Here, we used an attenuated strain of <em>Listeria monocytogenes</em> (<em>ΔactA</em>, Lm) that lacks tumor antigens to examine the immune response to Lm itself in tumor-bearing mice following intravenous (i.v.), intratumoral (i.t.), or combined i.v. + i.t. Lm delivery. Unexpectedly, i.t. Lm alone recruited neutrophils to tumors, which became immunosuppressive, provided an intracellular reservoir for long-term persistence of Lm in tumors, and promoted tumor growth. In contrast, prior i.v. Lm administration generated anti-Lm cytotoxic CD8<sup>+</sup> T cells that infiltrated tumors upon i.t. Lm delivery. These Lm-specific CD8<sup>+</sup> T cells control tumors by inducing cancer cell apoptosis, limiting cancer cell proliferation, and enhancing tumor antigen cross-presentation to tumor-specific T cells. Thus, an anti-Lm CD8<sup>+</sup> T cell response against Lm-colonized tumors can control cancer, offering a paradigm for cancer immunotherapy that leverages systemic CD8<sup>+</sup> T cell immunity targeting i.t. bacteria.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"17 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219121","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}
ImmunityPub Date : 2025-06-03DOI: 10.1016/j.immuni.2025.05.005
Weijue Li, Haoyang Zhu, Xiaoyu Zou, Hui Ye, Jia Zhong, Shasha Xiang, Yi Lou, Jiali Mao, Lingyun Qi, Xiawei Hu, Yan Zhang, Jinchao Hou, Bingduo Wang, Christian Bode, Andreas Hoeft, Xuekun Li, Kai Zhang, Marco Colonna, Xiangming Fang
{"title":"A brain-to-lung signal from GABAergic neurons to ADRB2+ interstitial macrophages promotes pulmonary inflammatory responses","authors":"Weijue Li, Haoyang Zhu, Xiaoyu Zou, Hui Ye, Jia Zhong, Shasha Xiang, Yi Lou, Jiali Mao, Lingyun Qi, Xiawei Hu, Yan Zhang, Jinchao Hou, Bingduo Wang, Christian Bode, Andreas Hoeft, Xuekun Li, Kai Zhang, Marco Colonna, Xiangming Fang","doi":"10.1016/j.immuni.2025.05.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.005","url":null,"abstract":"Severe pneumonia is predominantly caused by cytokine storms in the lung, but whether this process is controlled by the brain-lung axis remains unclear. Here, we found that GABAergic neurons in the central amygdala (CeA) were highly activated during severe pneumonia, which substantially contributed to inflammation and lung injury. Inhibition of CeA GABAergic neurons mitigated cytokine storms and improved survival rates in lethal pneumonia in mice. We uncovered a CeA-rostral ventrolateral medulla-sympathetic neural pathway connecting the brain to the lung, which enhanced norepinephrine (NE) release and amplified inflammatory signals. A subpopulation of β2-adrenergic receptor (ADRB2)<sup>+</sup> interstitial macrophages surrounding the pulmonary sympathetic nerves (PSNs) responded to elevated NE, which aggravated inflammation and lung injury during severe pneumonia. Specific inhibition of PSNs and ADRB2 signaling improved the outcomes of severe pneumonia. Our study identifies a crucial brain-to-lung sympathetic signal controlling macrophage-mediated lung inflammatory responses, which could be harnessed as a therapeutic strategy for severe pneumonia.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"41 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144202323","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":"Efflux of N1-acetylspermidine from hepatoma fosters macrophage-mediated immune suppression to dampen immunotherapeutic efficacy","authors":"Zheng-Yu Liu, Cai-Yuan Wu, Rui-Qi Wu, Jun-Cheng Wang, Chun-Xiang Huang, Xu-Yan Wang, Yaojun Zhang, Limin Zheng, Yun Chen, Xiang-Ming Lao, Dong-Ping Chen, Dong-Ming Kuang","doi":"10.1016/j.immuni.2025.05.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.006","url":null,"abstract":"Metabolic reprogramming is a hallmark of tumor progression. Here, we examined the metabolic profile of hepatocellular carcinoma (HCC), a disease that responds poorly to immune checkpoint blockade (ICB). Polyamine metabolism increased in HCC samples. Of the polyamine spectrum analyzed, N1-acetylspermidine (N1-Ac-Spd) accumulated in HCC tissue as compared with nontumoral liver tissue and was elevated in paired plasma. Injection of N1-Ac-Spd promoted tumor progression in preclinical models and compromised the efficacy of ICB. Inflammatory macrophages increased expression of the spermidine/spermine N1-acetyltransferase 1, SAT1, in hepatoma cells, leading to increased N1-Ac-Spd efflux via the polyamine transporter protein SLC3A2. Mechanistically, N1-Ac-Spd efflux activated SRC signaling in a charge-dependent manner, which in turn induced CCL1<sup>+</sup> macrophage polarization, the recruitment of CCR8<sup>+</sup> regulatory T cells, and an immunosuppressive tumor microenvironment (TME). <em>In vivo</em> interventions targeting SLC3A2, SAT1, or CCL1 enhanced the antitumor effects of ICB therapy. Our findings provide insight into the mechanisms whereby metabolic reprogramming fosters an immunosuppressive TME, with implications for the treatment of HCC.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"98 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192931","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}
ImmunityPub Date : 2025-05-30DOI: 10.1016/j.immuni.2025.05.002
Carlos H. Hiroki, Mortaza F. Hassanabad, Manon Defaye, Nicole Sarden, Alexandria Bartlett, Raquel Farias, Angela P. Nguyen, Idaira M. Guerrero-Fonseca, Grace Yoon, Luke Brown, Caixia Ma, Hyungjun Yang, Darrel Belke, Ali Fatehi Hassanabad, Christopher McCoy, Nicole L. Rosin, Dennis J. Orton, Paul W.M. Fedak, Bruce A. Vallance, Hongbing Yu, Bryan G. Yipp
{"title":"Nociceptor neurons suppress alveolar macrophage-induced Siglec-F+ neutrophil-mediated inflammation to protect against pulmonary fibrosis","authors":"Carlos H. Hiroki, Mortaza F. Hassanabad, Manon Defaye, Nicole Sarden, Alexandria Bartlett, Raquel Farias, Angela P. Nguyen, Idaira M. Guerrero-Fonseca, Grace Yoon, Luke Brown, Caixia Ma, Hyungjun Yang, Darrel Belke, Ali Fatehi Hassanabad, Christopher McCoy, Nicole L. Rosin, Dennis J. Orton, Paul W.M. Fedak, Bruce A. Vallance, Hongbing Yu, Bryan G. Yipp","doi":"10.1016/j.immuni.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.002","url":null,"abstract":"Pulmonary fibrosis results from persistent and pathological tissue repair, which is therapeutically challenging to attenuate and often fatal. The immune processes involved in fibrosis remain ill defined. Using a bleomycin-induced lung fibrosis murine model, we discovered that vagal TRPV1<sup>+</sup> nociceptors are protective. Pharmacological ablation or genetic deletion of nociceptors resulted in worsened fibrosis and outcomes. Without nociceptors, alveolar macrophages aberrantly produced vasoactive intestinal peptide (VIP), leading to cytokine TGF-β1-mediated alternative proinflammatory Siglec-F<sup>+</sup> neutrophil recruitment to the lung with a high propensity for neutrophil extracellular trap (NET) formation. VIP inhibition or <em>Vip</em> deletion in hematopoietic cells improved outcomes and attenuated Siglec-F<sup>+</sup> neutrophil recruitment to the lungs in nociceptor-deficient mice, while VIP administration had the opposite effect. Thus, nociceptors are essential regulators of inflammation during pulmonary fibrosis. These findings provide mechanistic insights into how the nervous system impacts the progression of fibrotic lung diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"36 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176667","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}
ImmunityPub Date : 2025-05-30DOI: 10.1016/j.immuni.2025.05.003
Jubayer Rahman, Jack A. Bibby, Parul Singh, Nicolas S. Merle, Erin E. West, Andrea Bohrer, Katrin Mayer-Barber, Chengyu Liu, Lauren R. Brinster, Behdad Afzali, Ana M. Briones, Sara Alehashemi, Farzana Bhuyan, Jiahui Ge, Xijian Chen, Yingbi Zhou, Murray C.H. Clarke, Bin Liu, Raphaela Goldbach-Mansky, C. Henrique Serezani, Claudia Kemper
{"title":"A CD4+ T cell-intrinsic complement C5aR2-prostacyclin-IL-1R2 axis orchestrates Th1 cell contraction","authors":"Jubayer Rahman, Jack A. Bibby, Parul Singh, Nicolas S. Merle, Erin E. West, Andrea Bohrer, Katrin Mayer-Barber, Chengyu Liu, Lauren R. Brinster, Behdad Afzali, Ana M. Briones, Sara Alehashemi, Farzana Bhuyan, Jiahui Ge, Xijian Chen, Yingbi Zhou, Murray C.H. Clarke, Bin Liu, Raphaela Goldbach-Mansky, C. Henrique Serezani, Claudia Kemper","doi":"10.1016/j.immuni.2025.05.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.003","url":null,"abstract":"T helper 1 (Th1) cell initiation pathways are well characterized; however, those regulating their contraction are less understood. Here, we define a CD4<sup>+</sup> T cell-autonomous pathway in which complement C5 orchestrated a shift from prostaglandin E2 (PGE2) dominance to enhanced prostacyclin (PGI2) production via activation of C5a receptor 2 (C5aR2). This pivot in lipid mediators induced autocrine signaling through the PGI2 receptor and expression of the interleukin-1 (IL-1) decoy IL-1 receptor type 2 (IL-1R2), which sequestered Th1 cell-driving intrinsic IL-1β, facilitating Th1 cell contraction. Disruption of this C5aR2-PGI2-R axis was a hallmark of pathologically persistent Th1 cell activity in inflammatory conditions, including cryopyrin-associated periodic syndromes (CAPS), Crohn’s disease, and rheumatoid arthritis. Rebalancing this axis through selective PGE2 synthase inhibition rectified the hyperactive Th1 cell phenotype <em>in vitro</em> in T cells from individuals with CAPS. Therefore, complement is a key controller of prostanoid metabolism, and the latter is an intrinsic—and potentially druggable—checkpoint for the cessation of Th1 cell effector responses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"172 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176669","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}
ImmunityPub Date : 2025-05-30DOI: 10.1016/j.immuni.2025.05.004
Patricia S. Grace, Joshua M. Peters, Jaimie Sixsmith, Richard Lu, Edward B. Irvine, Corinne Luedeman, Brooke A. Fenderson, Andrew Vickers, Matthew D. Slein, Tanya McKitrick, Mo-Hui Wei, Richard D. Cummings, Aaron Wallace, Lisa A. Cavacini, Alok Choudhary, Megan K. Proulx, Christopher Sundling, Gunilla Källenius, Rajko Reljic, Joel D. Ernst, Galit Alter
{"title":"Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction","authors":"Patricia S. Grace, Joshua M. Peters, Jaimie Sixsmith, Richard Lu, Edward B. Irvine, Corinne Luedeman, Brooke A. Fenderson, Andrew Vickers, Matthew D. Slein, Tanya McKitrick, Mo-Hui Wei, Richard D. Cummings, Aaron Wallace, Lisa A. Cavacini, Alok Choudhary, Megan K. Proulx, Christopher Sundling, Gunilla Källenius, Rajko Reljic, Joel D. Ernst, Galit Alter","doi":"10.1016/j.immuni.2025.05.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.004","url":null,"abstract":"<em>Mycobacterium tuberculosis</em>, the causative agent of tuberculosis (TB), a leading cause of death by an infectious disease globally, has no efficacious vaccine. Antibodies are implicated in <em>M. tuberculosis</em> control, but the mechanisms of action remain poorly understood. We assembled a library of monoclonal antibodies (mAb) and screened for <em>M. tuberculosis</em>-restrictive activity in mice, identifying protective antibodies targeting diverse antigens. To dissect the mechanism of mAb-mediated <em>M. tuberculosis</em> restriction, we optimized a protective lipoarabinomannan-specific mAb, generating Fc variants. <em>In vivo</em> analysis of these Fc variants revealed a role for Fc-effector function in <em>M. tuberculosis</em> restriction. Restrictive Fc variants altered distribution of <em>M. tuberculosis</em> across innate immune cells. Single-cell transcriptomics highlighted distinctly activated pathways within innate immune cell subpopulations, identifying early activation of neutrophils as a key signature of mAb-mediated <em>M. tuberculosis</em> restriction. Therefore, antibody-mediated restriction of <em>M. tuberculosis</em> is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"17 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176902","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}
ImmunityPub Date : 2025-05-28DOI: 10.1016/j.immuni.2025.05.022
Ruoxi Zhang, Chunhua Yu, Herbert J. Zeh, Haichao Wang, Guido Kroemer, Daniel J. Klionsky, Timothy R. Billiar, Rui Kang, Daolin Tang
{"title":"Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis","authors":"Ruoxi Zhang, Chunhua Yu, Herbert J. Zeh, Haichao Wang, Guido Kroemer, Daniel J. Klionsky, Timothy R. Billiar, Rui Kang, Daolin Tang","doi":"10.1016/j.immuni.2025.05.022","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.022","url":null,"abstract":"(Immunity <em>56</em>, 2736–2754.e1–e8; December 12, 2023)","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"19 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154284","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}
ImmunityPub Date : 2025-05-26DOI: 10.1016/j.immuni.2025.04.030
William D. Green, Amber Gomez, Alec L. Plotkin, Brandon M. Pratt, Emily F. Merritt, Genevieve N. Mullins, Nancy P. Kren, Jennifer L. Modliszewski, Vasyl Zhabotynsky, Mark G. Woodcock, Jarred M. Green, Gabrielle Cannon, Matthew E. Pipkin, Gianpietro Dotti, Jessica E. Thaxton, Yuliya Pylayeva-Gupta, Albert S. Baldwin, John P. Morris, Natalie Stanley, J. Justin Milner
{"title":"Enhancer-driven gene regulatory networks reveal transcription factors governing T cell adaptation and differentiation in the tumor microenvironment","authors":"William D. Green, Amber Gomez, Alec L. Plotkin, Brandon M. Pratt, Emily F. Merritt, Genevieve N. Mullins, Nancy P. Kren, Jennifer L. Modliszewski, Vasyl Zhabotynsky, Mark G. Woodcock, Jarred M. Green, Gabrielle Cannon, Matthew E. Pipkin, Gianpietro Dotti, Jessica E. Thaxton, Yuliya Pylayeva-Gupta, Albert S. Baldwin, John P. Morris, Natalie Stanley, J. Justin Milner","doi":"10.1016/j.immuni.2025.04.030","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.030","url":null,"abstract":"Tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory CD8<sup>+</sup> T cell (Trm) phenotype are associated with improved patient outcomes in solid malignancies. To define programs governing the formation of Trm-like TIL, we performed paired single-cell RNA sequencing and single-cell ATAC sequencing of T cell receptor (TCR)-matched CD8<sup>+</sup> T cells in models of infection and cancer. Enhancer-driven regulons assembled from multiomic profiling data revealed epigenetic and transcriptional programs regulating the formation of Trm-like TIL in relation to canonical exhausted and memory T cell states. The transcriptional regulator KLF2 repressed the formation of CD69<sup>+</sup>CD103<sup>+</sup> Trm-like TIL and limited anti-tumor activity. Conversely, sustained expression of the transcription factor BATF enhanced formation of CD69<sup>+</sup>CD103<sup>+</sup> TIL, contingent upon downregulation of KLF2. Transforming growth factor β (TGF-β) signaling and CD103 expression were necessary for Trm-like TIL formation, but BATF overexpression was sufficient to drive formation of CD69<sup>+</sup>CD103<sup>+</sup> TIL in TGFBR2-silenced cells. These findings reveal mechanisms of Trm-like TIL differentiation and provide a framework for considering tissue residency in the context of CD8<sup>+</sup> T cell heterogeneity in the tumor microenvironment.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"149 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137157","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}
ImmunityPub Date : 2025-05-19DOI: 10.1016/j.immuni.2025.04.029
Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R. Wijewardhane, Caitlin E. Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P. Jethava, Matthew G. Clark, Bin Dong, Seohee Ma, Gaurav Chopra
{"title":"Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease","authors":"Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R. Wijewardhane, Caitlin E. Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P. Jethava, Matthew G. Clark, Bin Dong, Seohee Ma, Gaurav Chopra","doi":"10.1016/j.immuni.2025.04.029","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.029","url":null,"abstract":"Microglial phagocytosis genes have been linked to increased risk for Alzheimer’s disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)—a key enzyme that converts FFAs to TGs—promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"121 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088103","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}
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