ImmunityPub Date : 2025-03-31DOI: 10.1016/j.immuni.2025.03.004
Motonao Osaki, Shimon Sakaguchi
{"title":"Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity","authors":"Motonao Osaki, Shimon Sakaguchi","doi":"10.1016/j.immuni.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.03.004","url":null,"abstract":"Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation <em>in vitro</em>. <em>In vivo</em>, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"31 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736967","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 : 2025-03-31DOI: 10.1016/j.immuni.2025.03.014
Jyothi N. Purushotham, Holly L. Lutz, Edyth Parker, Kristian G. Andersen
{"title":"Immunological drivers of zoonotic virus emergence, evolution, and endemicity","authors":"Jyothi N. Purushotham, Holly L. Lutz, Edyth Parker, Kristian G. Andersen","doi":"10.1016/j.immuni.2025.03.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.03.014","url":null,"abstract":"The disruption of natural ecosystems caused by climate change and human activity is amplifying the risk of zoonotic spillover, presenting a growing global health threat. In the past two decades, the emergence of multiple zoonotic viruses has exposed critical gaps in our ability to predict epidemic trajectories and implement effective interventions. RNA viruses, in particular, are challenging to control due to their high mutation rates and ability to adapt and evade immune defenses. To better prepare for future outbreaks, it is vital that we deepen our understanding of the factors driving viral emergence, transmission, and persistence in human populations. Specifically, deciphering the interactions between antibody-mediated immunity and viral evolution will be key. In this perspective, we explore these dynamic relationships and highlight research priorities that may guide the development of more effective strategies to mitigate the impact of emerging infectious diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"34 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737142","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 : 2025-03-31DOI: 10.1016/j.immuni.2025.03.003
Patrick J. Madden, Ester Marina-Zárate, Kristen A. Rodrigues, Jon M. Steichen, Monolina Shil, Kaiyuan Ni, Katarzyna Kaczmarek Michaels, Laura Maiorino, Amit A. Upadhyay, Swati Saha, Arpan Pradhan, Oleksandr Kalyuzhiny, Alessia Liguori, Paul G. Lopez, Ivy Phung, Claudia Flynn, Amelia Zhou, Mariane B. Melo, Ashley Lemnios, Nicole Phelps, Shane Crotty
{"title":"Diverse priming outcomes under conditions of very rare precursor B cells","authors":"Patrick J. Madden, Ester Marina-Zárate, Kristen A. Rodrigues, Jon M. Steichen, Monolina Shil, Kaiyuan Ni, Katarzyna Kaczmarek Michaels, Laura Maiorino, Amit A. Upadhyay, Swati Saha, Arpan Pradhan, Oleksandr Kalyuzhiny, Alessia Liguori, Paul G. Lopez, Ivy Phung, Claudia Flynn, Amelia Zhou, Mariane B. Melo, Ashley Lemnios, Nicole Phelps, Shane Crotty","doi":"10.1016/j.immuni.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.03.003","url":null,"abstract":"Rare naive B cells have special pathogen-recognition features that enable outsized contributions to protective immunity but infrequently participate in immune responses. We investigatee how germline-targeting vaccine delivery and adjuvant selection affect priming of exceptionally rare BG18-like HIV broadly neutralizing antibody-precursor B cells (<1-in-50 million) in non-human primates. Only escalating dose (ED) priming immunization using the saponin adjuvant SMNP elicited detectable BG18-like cells in germinal centers (GCs) compared with other conditions. All groups had strong GC responses, but only ED+SMNP and bolus+SMNP induced BG18-like memory B cells in >50% of animals. One group had vaccine-specific GC responses equivalent to ED+SMNP but scarce BG18-like B cells. Following homologous boosting, BG18-like memory B cells were present in a bolus priming group but with lower somatic hypermutation and affinities than ED+SMNP. This outcome inversely associated with post-prime antibody titers, suggesting antibody feedback significantly influences rare precursor B cell responses. Thus, antigen and inflammatory stimuli extensively impact priming and affinity maturation of rare B cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"29 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736966","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 : 2025-03-28DOI: 10.1016/j.immuni.2025.03.002
Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L. Chan, Bo Wei, Philip L. Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C. Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, Xiang H.-F. Zhang
{"title":"Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer","authors":"Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L. Chan, Bo Wei, Philip L. Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C. Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, Xiang H.-F. Zhang","doi":"10.1016/j.immuni.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.03.002","url":null,"abstract":"The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723819","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":"The transcription factor MEF2C restrains microglial overactivation by inhibiting kinase CDK2","authors":"Xiaodan Hu, Jianchen Wu, Lu Shi, Folin Wang, Kezhang He, Pengcheng Tan, Yanyan Hu, Yuanyuan Yang, Dan Wang, Tianhua Ma, Sheng Ding","doi":"10.1016/j.immuni.2025.02.026","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.02.026","url":null,"abstract":"Microglial intrinsic immune checkpoints are essential safeguards to maintain immune homeostasis by preventing microglial overactivation, a process that substantially influences neurological disorders such as autism spectrum disorder (ASD). MEF2C is a crucial immune checkpoint that regulates microglial activation, but the mechanism remains unclear. We found that <em>MEF2C</em>-deficient (<em>MEF2C</em><sup>−/−</sup>) induced microglia-like cells (iMGLs) derived from human pluripotent stem cells (hPSCs) exhibited overactivation following lipopolysaccharide stimulation, mimicking patterns observed in various neuroinflammatory disorders. High-throughput screening identified BMS265246, a cyclin-dependent kinase 2 (CDK2) inhibitor, which suppressed overactivation of <em>MEF2C</em><sup>−/−</sup> iMGLs and normalized their inflammatory responses. Mechanistically, MEF2C transcriptionally upregulated p21 to inhibit CDK2 activation-mediated retinoblastoma protein (RB) degradation, thereby preventing transcription factor nuclear factor κB (NFκB) nuclear translocation and consequent microglial overactivation. BMS265246 treatment substantially ameliorated microglial overactivation and ASD-like behaviors in <em>Mef2c</em>-deficient mice. Our findings identify the MEF2C-p21-CDK2-RB-NFκB axis as a critical pathway to maintain microglial homeostasis and highlight CDK2 as a potential therapeutic target for neuroinflammation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"35 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695433","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 : 2025-03-25DOI: 10.1016/j.immuni.2025.03.001
Alexander J. Nelson, Bruna K. Tatematsu, Jordan R. Beach, Dorothy K. Sojka, Yee Ling Wu
{"title":"Lung-resident memory B cells maintain allergic IgE responses in the respiratory tract","authors":"Alexander J. Nelson, Bruna K. Tatematsu, Jordan R. Beach, Dorothy K. Sojka, Yee Ling Wu","doi":"10.1016/j.immuni.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.03.001","url":null,"abstract":"Although allergen-specific immunoglobulin E (IgE) is a key mediator of allergic asthma, IgE-expressing B cells fail to form memory B cells (MBCs). Here, we studied the cellular mechanisms supporting IgE production in the respiratory tract. Allergen inhalation induced B cell infiltration into the lungs and IgE in the airway. Tracking B cells poised to class switch to IgE in reporter mice revealed predominant IgE class switching in the lung and identified IgG1<sup>+</sup> MBCs as precursors of IgE-producing cells, which was supported by B cell receptor (BCR) repertoire sequencing. B cells localized with CD4<sup>+</sup> T cells in peribronchiolar lymphoid aggregates. In coculture, interleukin-4 from lung Th2 cells induced lung MBCs to class switch to IgE. Lung-resident MBCs expanded after antigen rechallenge, concurrent with the emergence of IgE-secreting plasma cells (PCs), and the production of IgE in the airway was independent of systemic IgE in circulation, as indicated by parabiosis. Thus, lung-resident IgG1<sup>+</sup> MBCs are cellular precursors for IgE-secreting PCs in the respiratory mucosa.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"93 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695275","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 : 2025-03-25DOI: 10.1016/j.immuni.2025.02.027
François-Xavier Mauvais, Yamina Hamel, Aymeric Silvin, Kevin Mulder, Kai Hildner, Ramazan Akyol, Marc Dalod, Despoina Koumantou, Loredana Saveanu, Meriem Garfa, Nicolas Cagnard, Barbara Bertocci, Florent Ginhoux, Peter van Endert
{"title":"Metallophilic marginal zone macrophages cross-prime CD8+ T cell-mediated protective immunity against blood-borne tumors","authors":"François-Xavier Mauvais, Yamina Hamel, Aymeric Silvin, Kevin Mulder, Kai Hildner, Ramazan Akyol, Marc Dalod, Despoina Koumantou, Loredana Saveanu, Meriem Garfa, Nicolas Cagnard, Barbara Bertocci, Florent Ginhoux, Peter van Endert","doi":"10.1016/j.immuni.2025.02.027","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.02.027","url":null,"abstract":"Splenic metallophilic marginal zone macrophages (MMMs) are positioned to control the dissemination of blood-borne threats. We developed a purification protocol to enable characterization of MMMs phenotypically and transcriptionally. MMM gene expression profile was enriched for pathways associated with CD8<sup>+</sup> T cell activation and major histocompatibility complex class I (MHC class I) cross-presentation. <em>In vitro</em>, purified MMMs equaled conventional dendritic cells type 1 (cDC1s) in cross-priming CD8<sup>+</sup> T cells to soluble and particulate antigens, yet MMMs employed a distinct vacuolar processing pathway. <em>In vivo</em> biphoton and <em>ex vivo</em> light-sheet imaging showed long-standing contacts with cognate T cells differentiating to effectors. MMMs cross-primed protective CD8<sup>+</sup> T cell antitumor responses both by capturing blood-borne tumor antigens and by internalizing tumor cells seeding the spleen. This cross-priming required expression of the transcription factor Batf3 by MMMs but was independent of cDC1-mediated capture of tumor material for cross-presentation or MHC class I-dressing. Thus, MMMs combine control of the dissemination of blood-borne pathogens and tumor materials with the initiation of innate and adaptive responses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"35 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695276","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 : 2025-03-24DOI: 10.1016/j.immuni.2025.02.024
Matija Zelic, Anna Blazier, Fabrizio Pontarelli, Michael LaMorte, Jeremy Huang, Ozge E. Tasdemir-Yilmaz, Yi Ren, Sean K. Ryan, Cynthia Shapiro, Caroline Morel, Pavithra Krishnaswami, Mikhail Levit, Disha Sood, Yao Chen, Joseph Gans, Xinyan Tang, Jennifer Hsiao-Nakamoto, Fen Huang, Bailin Zhang, James D. Berry, Timothy R. Hammond
{"title":"Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis","authors":"Matija Zelic, Anna Blazier, Fabrizio Pontarelli, Michael LaMorte, Jeremy Huang, Ozge E. Tasdemir-Yilmaz, Yi Ren, Sean K. Ryan, Cynthia Shapiro, Caroline Morel, Pavithra Krishnaswami, Mikhail Levit, Disha Sood, Yao Chen, Joseph Gans, Xinyan Tang, Jennifer Hsiao-Nakamoto, Fen Huang, Bailin Zhang, James D. Berry, Timothy R. Hammond","doi":"10.1016/j.immuni.2025.02.024","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.02.024","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation is prominent in ALS, but the cell state dynamics and pathways driving disease remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords and identified altered glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on the inflammation and cell death regulator receptor-interacting protein kinase 1 (RIPK1) and the necroptotic cell death pathway. In superoxide dismutase 1 (SOD1)<sup>G93A</sup> mice, blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses. We used human induced pluripotent stem cell (iPSC)-derived motor neuron, astrocyte, and microglia tri-cultures to identify potential biomarkers that are secreted upon RIPK1 activation <em>in vitro</em> and modulated by RIPK1 inhibition in the cerebrospinal fluid (CSF) of people with ALS. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"25 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677861","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 : 2025-03-24DOI: 10.1016/j.immuni.2025.02.025
Jenna J. Guthmiller, Linda Yu-Ling Lan, Lei Li, Yanbin Fu, Sean A. Nelson, Carole Henry, Christopher T. Stamper, Henry A. Utset, Alec W. Freyn, Julianna Han, Olivia Stovicek, Jiaolong Wang, Nai-Ying Zheng, Min Huang, Haley L. Dugan, Micah E. Tepora, Xueyong Zhu, Yao-Qing Chen, Anna-Karin E. Palm, Dustin G. Shaw, Patrick C. Wilson
{"title":"Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins","authors":"Jenna J. Guthmiller, Linda Yu-Ling Lan, Lei Li, Yanbin Fu, Sean A. Nelson, Carole Henry, Christopher T. Stamper, Henry A. Utset, Alec W. Freyn, Julianna Han, Olivia Stovicek, Jiaolong Wang, Nai-Ying Zheng, Min Huang, Haley L. Dugan, Micah E. Tepora, Xueyong Zhu, Yao-Qing Chen, Anna-Karin E. Palm, Dustin G. Shaw, Patrick C. Wilson","doi":"10.1016/j.immuni.2025.02.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.02.025","url":null,"abstract":"In a phase 1 clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved hemagglutinin (HA) stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single-cell RNA sequencing and B cell receptor repertoire sequencing. We have shown that the cHA-inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At 1 year post immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"49 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677860","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 : 2025-03-20DOI: 10.1016/j.immuni.2025.02.023
Isidoro Cobo, Jessica Murillo, Mohnish Alishala, Stephen Calderon, Roxana Coras, Benjamin Hemming, Faith Inkum, Fiorella Rosas, Riku Takei, Nathan Spann, Thomas A. Prohaska, Paulo V.G. Alabarse, Se-Jin Jeong, Christian K. Nickl, Anyan Cheng, Benjamin Li, Andrea Vogel, Thomas Weichhart, José J. Fuster, Thomas Le, Christopher K. Glass
{"title":"Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression","authors":"Isidoro Cobo, Jessica Murillo, Mohnish Alishala, Stephen Calderon, Roxana Coras, Benjamin Hemming, Faith Inkum, Fiorella Rosas, Riku Takei, Nathan Spann, Thomas A. Prohaska, Paulo V.G. Alabarse, Se-Jin Jeong, Christian K. Nickl, Anyan Cheng, Benjamin Li, Andrea Vogel, Thomas Weichhart, José J. Fuster, Thomas Le, Christopher K. Glass","doi":"10.1016/j.immuni.2025.02.023","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.02.023","url":null,"abstract":"Exposure to particles is a driver of several inflammatory diseases. Here, we investigated macrophage responses to monosodium urate crystals, calcium pyrophosphate crystals, aluminum salts, and silica nanoparticles. While each particle induced a distinct gene expression pattern, we identified a common inflammatory signature and acute activation of lysosomal acidification genes. Using monosodium urate crystals as a model, we demonstrated that this lysosomal gene program is regulated by a 5′-prime-AMP-activated protein kinase (AMPK)-dependent transcriptional network, including TFEB, TFE3, and the epigenetic regulators DNA methyl transferase 3a (DNMT3A) and DOT1L. This lysosomal acidification program operates in parallel with, but largely independently of, a JNK-AP-1-dependent network driving crystal-induced chemokine and cytokine expression. These findings reveal a bifurcation in pathways governing inflammatory and lysosomal responses, offering insights for treating particle-associated diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"183 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660419","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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