Åsa Johansson, Mahadevan Venkita Subramani, Bahtiyar Yilmaz, Elisabeth E L Nyström, Elena Layunta, Liisa Arike, Felix Sommer, Philip Rosenstiel, Lars Vereecke, Louise Mannerås-Holm, Andy Wullaert, Thaher Pelaseyed, Malin E V Johansson, George M H Birchenough
{"title":"Neonatal microbiota colonization primes maturation of goblet cell-mediated protection in the pre-weaning colon.","authors":"Åsa Johansson, Mahadevan Venkita Subramani, Bahtiyar Yilmaz, Elisabeth E L Nyström, Elena Layunta, Liisa Arike, Felix Sommer, Philip Rosenstiel, Lars Vereecke, Louise Mannerås-Holm, Andy Wullaert, Thaher Pelaseyed, Malin E V Johansson, George M H Birchenough","doi":"10.1084/jem.20241591","DOIUrl":"https://doi.org/10.1084/jem.20241591","url":null,"abstract":"<p><p>Regulated host-microbe interactions are a critical aspect of lifelong health. Colonic goblet cells protect from microorganisms via the generation of a mucus barrier structure. Bacteria-sensing sentinel goblet cells provide secondary protection by orchestrating mucus secretion when microbes breach the mucus barrier. Mucus deficiencies in germ-free mice implicate a role for the microbiota in programming barrier generation, but its natural ontogeny remains undefined. We now investigate the mucus barrier and sentinel goblet cell development in relation to postnatal colonization. Combined in vivo and ex vivo analyses demonstrate rapid and sequential microbiota-dependent development of these primary and secondary goblet cell protective functions, with dynamic changes in mucus processing dependent on innate immune signaling via MyD88 and development of functional sentinel goblet cells dependent on the NADPH/dual oxidase family member Duox2. Our findings identify new mechanisms of microbiota-goblet cell regulatory interaction and highlight the critical importance of the pre-weaning period for the normal development of protective systems that are key legislators of host-microbiota interaction.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022060","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}
Endi K Santosa, Jennifer M Zhang, John C Sauter, Mariah E Lee, Brandon D Ng, Sigrun V Stulz, Meril Takizawa, Simon Grassmann, Orr-El Weizman, Nicholas M Adams, Ronan Chaligné, Annette Oxenius, Georg Gasteiger, Colleen M Lau, Joseph C Sun
{"title":"Defining molecular circuits of CD8+ T cell responses in tissues during latent viral infection.","authors":"Endi K Santosa, Jennifer M Zhang, John C Sauter, Mariah E Lee, Brandon D Ng, Sigrun V Stulz, Meril Takizawa, Simon Grassmann, Orr-El Weizman, Nicholas M Adams, Ronan Chaligné, Annette Oxenius, Georg Gasteiger, Colleen M Lau, Joseph C Sun","doi":"10.1084/jem.20242078","DOIUrl":"10.1084/jem.20242078","url":null,"abstract":"<p><p>Latent viral infections rely on a precise coordination of the immune response to control sporadic viral reactivation. CD8+ T cells play a crucial role in controlling viral latency by generating diverse memory responses in an epitope-specific manner. Among these distinct responses, conventional and inflationary memory responses have been described during herpesvirus infections. Using a newly generated TCR transgenic mouse strain, we investigated the transcriptomic and epigenetic remodeling of distinct epitope-specific CD8+ T cells during CMV infection across tissues at both population and single-cell levels. Our findings reveal that whereas the transcriptomic and epigenetic landscapes of conventional and inflationary memory responses diverge in the spleen and liver, these molecular programs converge in the salivary gland, a site of CMV persistence. Thus, we provide evidence that the dynamics of memory CD8+ T cell responses are distinct between tissues.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093733","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}
Riccardo Castagnoli, Francesca Pala, Poorani Subramanian, Cihan Oguz, Benjamin Schwarz, Ai Ing Lim, Andrew S Burns, Elena Fontana, Marita Bosticardo, Cristina Corsino, Angelina Angelova, Ottavia M Delmonte, Heather Kenney, Deanna Riley, Grace Smith, Lisa Ott de Bruin, Vasileios Oikonomou, Lucas Dos Santos Dias, Danielle Fink, Eric Bohrnsen, Cole D Kimzey, Gian Luigi Marseglia, Guisela Alva-Lozada, Jenna R E Bergerson, Ana Brett, Karlla W Brigatti, Dimana Dimitrova, Cullen M Dutmer, Alexandra F Freeman, Hanadys Ale, Steven M Holland, Francesco Licciardi, Srdjan Pasic, Laura E Poskitt, David E Potts, Joseph F Dasso, Svetlana O Sharapova, Kevin A Strauss, Brant R Ward, Melis Yilmaz, Douglas B Kuhns, Michail S Lionakis, Stephen R Daley, Heidi H Kong, Julia A Segre, Anna Villa, Stefania Pittaluga, Jolan E Walter, Ivan Vujkovic-Cvijin, Yasmine Belkaid, Luigi D Notarangelo
{"title":"Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency.","authors":"Riccardo Castagnoli, Francesca Pala, Poorani Subramanian, Cihan Oguz, Benjamin Schwarz, Ai Ing Lim, Andrew S Burns, Elena Fontana, Marita Bosticardo, Cristina Corsino, Angelina Angelova, Ottavia M Delmonte, Heather Kenney, Deanna Riley, Grace Smith, Lisa Ott de Bruin, Vasileios Oikonomou, Lucas Dos Santos Dias, Danielle Fink, Eric Bohrnsen, Cole D Kimzey, Gian Luigi Marseglia, Guisela Alva-Lozada, Jenna R E Bergerson, Ana Brett, Karlla W Brigatti, Dimana Dimitrova, Cullen M Dutmer, Alexandra F Freeman, Hanadys Ale, Steven M Holland, Francesco Licciardi, Srdjan Pasic, Laura E Poskitt, David E Potts, Joseph F Dasso, Svetlana O Sharapova, Kevin A Strauss, Brant R Ward, Melis Yilmaz, Douglas B Kuhns, Michail S Lionakis, Stephen R Daley, Heidi H Kong, Julia A Segre, Anna Villa, Stefania Pittaluga, Jolan E Walter, Ivan Vujkovic-Cvijin, Yasmine Belkaid, Luigi D Notarangelo","doi":"10.1084/jem.20241993","DOIUrl":"https://doi.org/10.1084/jem.20241993","url":null,"abstract":"<p><p>Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017905","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}
{"title":"\"What's in a name?\" Clarifying the identity of RORγt+ antigen-presenting cells.","authors":"Feiya Ou, Kenneth M Murphy","doi":"10.1084/jem.20250760","DOIUrl":"https://doi.org/10.1084/jem.20250760","url":null,"abstract":"<p><p>Recent publications have demonstrated that antigen-presenting cells (APCs) targeted by Rorc-cre (also known as RORγt-cre) are required for the induction of peripheral regulatory T (pTreg) cells in response to commensal and dietary antigens. In this issue of JEM, Sun et al. (https://doi.org/10.1084/jem.20250573) provide key insights into the identity of these cells, revealing that Rorc-cre-traced APCs include group 3 innate lymphoid cells (ILC3s), dendritic cells (DCs), and extrathymic AIRE-expressing cells (eTACs). Their work highlights eTACs as critical for inducing RORγt+ pTregs specific to food antigens, while implicating DCs in the generation of RORγt- pTregs.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078303","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}
Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, Sophie Panigot, Daiki Mori, Liaoxun Lu, Guillaume Voisinne, Carine Vilarnau Wolek, Marielle Mello, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Frédéric Fiore, Romain Roncagalli, Yinming Liang, Marie Malissen, Bernard Malissen
{"title":"A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.","authors":"Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, Sophie Panigot, Daiki Mori, Liaoxun Lu, Guillaume Voisinne, Carine Vilarnau Wolek, Marielle Mello, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Frédéric Fiore, Romain Roncagalli, Yinming Liang, Marie Malissen, Bernard Malissen","doi":"10.1084/jem.20250339","DOIUrl":"10.1084/jem.20250339","url":null,"abstract":"<p><p>Naive T cell activation requires both TCR and CD28 signals. The CARMIL2 cytosolic protein enables CD28-dependent activation of the NF-κB transcription factor via its ability to link CD28 to the CARD11 adaptor protein. Here, we developed mice expressing a mutation named Carmil2QE and mimicking a mutation found in human T cell malignancies. Naive T cells from Carmil2QE mice contained preformed CARMIL2QE-CARD11 complexes in numbers comparable to those assembling in wild-type T cells after CD28 engagement. Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly induced most of the functions that normally result from CD28 engagement in a manner that remains antigen-dependent. In turn, tumor-specific T cells expressing Carmil2QE do not require CD28 engagement and thereby escape to both PD-1 and CTLA-4 inhibition. In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those triggered by CD28 and exploited them to induce potent solid tumor-specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119625","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}
Ana Cardoso, Michael D Buck, Bruno Frederico, Probir Chakravarty, Oliver Schulz, Kok Haw Jonathan Lim, Cécile Piot, Mariana Pereira da Costa, Evangelos Giampazolias, Francesca Gasparrini, Neil Rogers, Caetano Reis E Sousa
{"title":"DNGR-1 regulates proliferation and migration of bone marrow dendritic cell progenitors.","authors":"Ana Cardoso, Michael D Buck, Bruno Frederico, Probir Chakravarty, Oliver Schulz, Kok Haw Jonathan Lim, Cécile Piot, Mariana Pereira da Costa, Evangelos Giampazolias, Francesca Gasparrini, Neil Rogers, Caetano Reis E Sousa","doi":"10.1084/jem.20241813","DOIUrl":"10.1084/jem.20241813","url":null,"abstract":"<p><p>Conventional dendritic cells (cDCs) are sentinel cells that play a crucial role in both innate and adaptive immune responses. cDCs originate from a progenitor (pre-cDC) in the bone marrow (BM) that travels via the blood to seed peripheral tissues before locally differentiating into functional cDC1 and cDC2 cells, as part of a process known as cDCpoiesis. How cDCpoiesis is regulated and whether this affects the output of cDCs is poorly understood. In this study, we show that DNGR-1, an innate immune receptor expressed by cDC progenitors and type 1 cDCs, can regulate cDCpoiesis in mice. In a competitive chimera setting, cDC progenitors lacking DNGR-1 exhibit increased proliferation and tissue migratory potential. Compared with their WT counterparts, DNGR-1-deficient cDC progenitor cells display superior colonization of peripheral tissues but an altered distribution. These findings suggest that cDCpoiesis can be regulated in part by precursor cell-intrinsic processes driven by signals from innate immune receptors such as DNGR-1 that may respond to alterations in the BM milieu.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12071193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012811","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}
Im-Hong Sun, Anita E Qualls, Han S Yin, Jiaxi Wang, Matthew P Arvedson, Joe Germino, Nolan K Horner, Sheng Zhong, Juan Du, Martin Valdearcos, Vasilis Ntranos, Richard M Locksley, Roberto R Ricardo-Gonzalez, James M Gardner
{"title":"RORγt eTACs mediate oral tolerance and Treg induction.","authors":"Im-Hong Sun, Anita E Qualls, Han S Yin, Jiaxi Wang, Matthew P Arvedson, Joe Germino, Nolan K Horner, Sheng Zhong, Juan Du, Martin Valdearcos, Vasilis Ntranos, Richard M Locksley, Roberto R Ricardo-Gonzalez, James M Gardner","doi":"10.1084/jem.20250573","DOIUrl":"https://doi.org/10.1084/jem.20250573","url":null,"abstract":"<p><p>The immune system must distinguish pathogens from innocuous dietary antigens, but the precise mechanisms and cellular actors remain unclear. Here, we demonstrate that RORγt-lineage APCs are required for oral tolerance. Using lineage tracing and single-cell sequencing, we show these APCs consist of three principal populations: type 3 innate lymphoid cells (ILC3s), RORγt-lineage dendritic cells, and cells expressing Aire called RORγt eTACs (R-eTACs)-also known as Janus or Thetis cells. We show that R-eTACs, but not ILC3s, are required for oral tolerance induction. We find R-eTACs are of probable myeloid origin and uniquely express integrin β8 (Itgb8). Both MHCII and Itgb8 expression in RORγt-lineage cells are necessary to induce food-specific regulatory T cells. Mice lacking R-eTACs or with deletion of MHCII or Itgb8 in the RORγt lineage fail to generate Tregs and instead develop a T-follicular helper response with elevated antigen-specific antibodies. These findings establish R-eTACs as critical mediators of oral tolerance and suggest novel cellular targets to modulate immune tolerance.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022562","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}
Flavia T T Antunes, Maria A Gandini, Agustin Garcia-Caballero, Sun Huang, Md Yousof Ali, Eder Gambeta, Ivana A Souza, Erika K Harding, Laurent Ferron, Asbjorg Stray-Pedersen, Vinicius M Gadotti, Gerald W Zamponi
{"title":"A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain.","authors":"Flavia T T Antunes, Maria A Gandini, Agustin Garcia-Caballero, Sun Huang, Md Yousof Ali, Eder Gambeta, Ivana A Souza, Erika K Harding, Laurent Ferron, Asbjorg Stray-Pedersen, Vinicius M Gadotti, Gerald W Zamponi","doi":"10.1084/jem.20241877","DOIUrl":"10.1084/jem.20241877","url":null,"abstract":"<p><p>Cav3.2 T-type calcium channels and their dysregulation by the deubiquitinase USP5 contribute to development of inflammatory and neuropathic pain. We report on a pediatric patient with a de novo heterozygous missense mutation R24W in USP5 who exhibits pain insensitivity. We created a CRISPR knock-in mouse harboring this mutation and performed detailed behavioral analyses in acute and chronic pain models. Heterozygous R24W mice of both sexes are resistant to acute pain and to thermal hypersensitivity in chronic inflammatory and neuropathic pain models. In contrast, only male R24W mice confer resistance to development of mechanical hypersensitivity. R24W mice lack upregulation of Cav3.2 and USP5 that is normally observed with CFA-induced inflammation. Moreover, mutant USP5 exhibits a dramatic reduction in enzymatic activity but stronger interactions with Cav3.2. Hence, R24W mutant USP5 is a critical regulator of chronic and acute pain states in humans by acting as a dominant-negative regulator of Cav3.2. Our data validate USP5 as a potential therapeutic target for chronic pain in humans.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078343","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}
Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng
{"title":"BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells.","authors":"Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng","doi":"10.1084/jem.20241133","DOIUrl":"https://doi.org/10.1084/jem.20241133","url":null,"abstract":"<p><p>In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor-exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of ∼216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021147","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}
Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee
{"title":"Gut dysbiosis from high-salt diet promotes glioma via propionate-mediated TGF-β activation.","authors":"Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee","doi":"10.1084/jem.20241135","DOIUrl":"10.1084/jem.20241135","url":null,"abstract":"<p><p>The purpose of this study is to investigate the impact of a high-salt diet (HSD), which is commonly found in Western countries, on the progression of glioma. Our research shows that the alterations in gut microbiota caused by an HSD facilitated the development of glioma. Mice fed an HSD have elevated levels of intestinal propionate, which accelerated the growth of glioma cells. We also find that propionate supplementation enhanced the response of glioma cells to low oxygen levels. Moreover, we identify a link between TGF-β signaling, response to low oxygen levels, and invasion-related pathways. Propionate treatment increases the expression of HIF-1α, leading to an increase in TGF-β1 production. Additionally, propionate treatment promotes glioma cell invasion through TGF-β signaling. Our findings suggest that an HSD-induced increase in propionate plays a crucial role in glioma progression by facilitating invasion through the hypoxic response and TGF-β signaling pathways, thereby establishing a significant connection between gut microbiota and the progression of glioma.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119809","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}
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