{"title":"Ciliated cell-derived IL-17D restrains allergic asthma through controlling monocyte recruitment.","authors":"Lei Yuan, Jinling Huang, Jianhui Chen, Tian Xie, Genyu Wang, Bowen Xie, Lei Qin, Yongzhen Chen, Xuan Zhong, Zixuan Zhao, Zhilin Peng, Xiaoshuang Wang, Miao Xu, Jing Ge, Xiaohu Wang, Chen Dong","doi":"10.1084/jem.20242328","DOIUrl":"https://doi.org/10.1084/jem.20242328","url":null,"abstract":"<p><p>The airway epithelium plays a crucial role in maintaining lung homeostasis, and its dysregulation is often linked to various lung diseases, including asthma. Ciliated cells, abundantly present in the mammalian airway epithelium, have a critical function in clearing inhaled particles and pathogens. We show here that ciliated cells constitutively express IL-17D, which functions as an immune brake in limiting allergic inflammation in murine models of asthma. Mechanistically, IL-17D functions to prevent influx of classical monocytes into the lung and their subsequent conversion to pathogenic alveolar macrophages, through binding to CD93. Deficiency in Il17d or Cd93 increased the expression of chemokine receptors on classical monocytes, including CCR6, thereby enhancing their recruitment to the lung and type 2 inflammation. Our study thus reveals an unexpected protective role of ciliated cells and IL-17D in lung immune responses and asthma, which can be further explored for treating related diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784406","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":"Taking the STING out of neurodegenerative disease.","authors":"Aman Mangalmurti, John R Lukens","doi":"10.1084/jem.20250951","DOIUrl":"10.1084/jem.20250951","url":null,"abstract":"<p><p>New work from Yang et al. (https://doi.org/10.1084/jem.20242296) provides an exhaustive study of a novel mouse model of NGLY1 deficiency, a devastating neurological disease, and implicates the cGAS-STING pathway in mediating key disease features which can be rescued using an orally administered STING antagonist.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612173","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}
Harry B Gristick, Harald Hartweger, Yoshiaki Nishimura, Edem Gavor, Kaito Nagashima, Nicholas S Koranda, Priyanthi N P Gnanapragasam, Leesa M Kakutani, Luisa N Segovia, Olivia K Donau, Jennifer R Keeffe, Anthony P West, Malcolm A Martin, Michel C Nussenzweig, Pamela J Bjorkman
{"title":"Design and characterization of HIV-1 vaccine candidates to elicit antibodies targeting multiple epitopes.","authors":"Harry B Gristick, Harald Hartweger, Yoshiaki Nishimura, Edem Gavor, Kaito Nagashima, Nicholas S Koranda, Priyanthi N P Gnanapragasam, Leesa M Kakutani, Luisa N Segovia, Olivia K Donau, Jennifer R Keeffe, Anthony P West, Malcolm A Martin, Michel C Nussenzweig, Pamela J Bjorkman","doi":"10.1084/jem.20250693","DOIUrl":"10.1084/jem.20250693","url":null,"abstract":"<p><p>A primary goal in the development of an AIDS vaccine is the elicitation of broadly neutralizing antibodies (bNAbs) that protect against diverse HIV-1 strains. To this aim, germline-targeting immunogens have been developed to activate bNAb precursors and initiate the induction of bNAbs. While most preclinical germline-targeting HIV-1 vaccine candidates only include a single bNAb precursor epitope, an effective HIV-1 vaccine will likely require bNAbs that target multiple epitopes on Env. Here, we report a newly designed germline-targeting Env SOSIP trimer, named 3nv.2, that presents three bNAb epitopes on Env: the CD4bs, V3, and V2 epitopes. 3nv.2 forms a stable trimeric Env and binds to bNAb precursors from each of the desired epitopes. Immunization experiments in rhesus macaques and mice demonstrate 3nv.2 elicits the combined effects of its parent immunogens. Our results provide proof of concept for using a germline-targeting immunogen presenting three or more bNAb epitopes and a framework to develop improved next-generation HIV-1 vaccine candidates.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821513","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":"Monoallelic mutations in MMD2 cause autosomal dominant aggressive periodontitis.","authors":"Tomoyuki Iwata, Yoko Mizoguchi, Tetsuya Yoshimoto, Miyuki Tsumura, Fumiaki Sakura, Jeffrey R Johnson, Shinji Matsuda, Kazuhisa Ouhara, Yukiko Nagatani, Takaki Asano, Hidenori Ohnishi, Zenichiro Kato, Keichiro Mihara, Hirokazu Kanegane, Tomoya Ueda, Shinya Sasaki, Yuri Taniguchi, Yurika Ninomiya, Yoshinori Ohno, Kyoko Suzuki-Takedachi, Yusuke Sotomaru, Tetsushi Sakuma, Takashi Yamamoto, Yukiko Matsuda, Kodai Kume, Terukazu Sanui, Fusanori Nishimura, Mikihito Kajiya, Yasuyoshi Ueki, Hidemi Kurihara, Hiroyuki Morino, Satoshi Okada, Hideshi Kawakami, Noriyoshi Mizuno","doi":"10.1084/jem.20231911","DOIUrl":"10.1084/jem.20231911","url":null,"abstract":"<p><p>Aggressive periodontitis causes rapid destruction of periodontal tissue. It occurs at a young age with familial clustering. We report on the first time on molecular and cellular basis of a Mendelian form of autosomal dominant aggressive periodontitis. Monoallelic mutations in the monocyte to macrophage differentiation-associated 2 (MMD2) gene, encoding MMD2, in two Japanese families with autosomal dominant aggressive periodontitis are identified. Mutations, c.347 C>T (p.A116V) and c.377 G>C (p.R126P) in MMD2, disturbed fMLP-induced activation of Ras/ERK signaling. Additionally, abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 mutation. Our studies revealed that monoallelic mutations in MMD2 underlie the impairment of neutrophil chemotaxis, which leads to the development of autosomal dominant aggressive periodontitis.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637124","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}
Heather J Faust, Margaret H Chang, A Helena Jonsson, Erin Theisen, Nelson M LaMarche, William V Trim, Lydia Lynch, Peter A Nigrovic, Michael B Brenner
{"title":"Adipose tissue harbors pathogenic T cells in obesity that exacerbate inflammatory arthritis.","authors":"Heather J Faust, Margaret H Chang, A Helena Jonsson, Erin Theisen, Nelson M LaMarche, William V Trim, Lydia Lynch, Peter A Nigrovic, Michael B Brenner","doi":"10.1084/jem.20240677","DOIUrl":"10.1084/jem.20240677","url":null,"abstract":"<p><p>Obesity worsens inflammatory arthritis severity, even in non-load-bearing joints, but the mechanism is unknown. Here, we show that there is an immunological mechanism mediated by T cells in adipose tissue. Using an antigen-induced arthritis model with trackable, arthritis-inducing CD8+ OT-I T cells, we found that OT-I T cells home to visceral adipose tissue (VAT) and expand there in the obese high-fat diet (HFD) context. Transplant of VAT from arthritic mice increased arthritis severity in naïve recipient mice and was ameliorated by CD8 T cell depletion. Bulk RNA sequencing identified pro-inflammatory changes to OT-I T cells in VAT characterized by increased IFN α and γ signaling after HFD. Intraperitoneal injection of IFNα, but not IFNγ, expanded CD8 T cell numbers in VAT. HFD-induced expansion of VAT CD8 T cells was ameliorated with global Ifnar1 deletion, and importantly, genetic deletion of Ifnar1 in T cells decreased arthritis severity in obese mice. These results provide a mechanistic explanation of how obesity worsens autoimmunity.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575616","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}
Sangya Chatterjee, Tamina Rückert, Ina Martin, Elisa Michaeli, Joerg Buescher, Petya Apostolova, Daniel Erny, Maria-Eleni Lalioti, Francesca Biavasco, Alina Hartmann, Solveig Runge, Lukas M Braun, Nana Talvard-Balland, Rachael C Adams, Annette Schmitt-Graeff, James Cook, Valentin Wenger, Dimitrios Athanassopoulos, Dilara Hasavci, Alexander Paolo Vallejo-Janeta, Thomas Blank, Philipp Schaible, Janaki Manoja Vinnakota, Alexander Zähringer, Stephanie C Ganal-Vonarburg, Wolfgang Melchinger, Dietmar Pfeifer, Natalie Köhler, Stephan P Rosshart, David Michonneau, Gérard Socié, Geoffroy Andrieux, Nina Cabezas-Wallscheid, Melanie Boerries, Marco Prinz, Robert Zeiser
{"title":"Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.","authors":"Sangya Chatterjee, Tamina Rückert, Ina Martin, Elisa Michaeli, Joerg Buescher, Petya Apostolova, Daniel Erny, Maria-Eleni Lalioti, Francesca Biavasco, Alina Hartmann, Solveig Runge, Lukas M Braun, Nana Talvard-Balland, Rachael C Adams, Annette Schmitt-Graeff, James Cook, Valentin Wenger, Dimitrios Athanassopoulos, Dilara Hasavci, Alexander Paolo Vallejo-Janeta, Thomas Blank, Philipp Schaible, Janaki Manoja Vinnakota, Alexander Zähringer, Stephanie C Ganal-Vonarburg, Wolfgang Melchinger, Dietmar Pfeifer, Natalie Köhler, Stephan P Rosshart, David Michonneau, Gérard Socié, Geoffroy Andrieux, Nina Cabezas-Wallscheid, Melanie Boerries, Marco Prinz, Robert Zeiser","doi":"10.1084/jem.20242180","DOIUrl":"https://doi.org/10.1084/jem.20242180","url":null,"abstract":"<p><p>Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584081","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}
Sophia Liu, Margarida Saraiva, Caroline R Bartman, Nathalie Saurat, Pamela C Rosato, Paula Licona-Limon, Alejandra Mendoza, Jenna Guthmiller, Coraline Mlynarczyk, Emily Goldberg
{"title":"Women in STEM becoming independent: People should feel free to be themselves and do great science.","authors":"Sophia Liu, Margarida Saraiva, Caroline R Bartman, Nathalie Saurat, Pamela C Rosato, Paula Licona-Limon, Alejandra Mendoza, Jenna Guthmiller, Coraline Mlynarczyk, Emily Goldberg","doi":"10.1084/jem.20251386","DOIUrl":"https://doi.org/10.1084/jem.20251386","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799291","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}
Jorden I Lane, Elida Nieves-Ortiz, Ornella Ndatabaye, Aliia R Fatkhullina, Sebastian Lopez, Terence S Dermody, Daria Esterházy
{"title":"Intestinal lymphatic vasculature is functionally adapted to different drainage regions and is altered by helminth infection.","authors":"Jorden I Lane, Elida Nieves-Ortiz, Ornella Ndatabaye, Aliia R Fatkhullina, Sebastian Lopez, Terence S Dermody, Daria Esterházy","doi":"10.1084/jem.20241181","DOIUrl":"10.1084/jem.20241181","url":null,"abstract":"<p><p>We sought to determine whether the lymphatic vasculature functionally adapts to the organ in which it resides, such as along the gut. Duodenal lymphatic capillaries (lacteals) displayed the most discontinuous tight junction composition within the gut, resulting in a dependence on duodenal lacteals for rapid dietary lipid uptake. Duodenal helminths abrogated these features. Parallel RNA sequencing of lymphatic endothelial cells and mucosa along the intestine revealed that the transcriptomes overlapped in functional profiles. RNA sequencing also identified a putative VEGFR-2/3 signaling gradient that may explain differences in lacteal tight junctions along the small intestine at homeostasis. Transcriptionally, helminth infection triggered antimicrobial and angiogenic responses. While microbial depletion acted additively to helminths on lymphatic restructuring, glucocorticoids partially reversed helminth-induced lacteal changes. This suggests helminths induce lymphangiogenesis and associated lymphatic \"zippering\" via inflammation. Our study uncovers and explains the superior lipid absorption by duodenal lacteals and how it is compromised by helminths and provides transcriptional insights into lymphatic function along the gut.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284907","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}
Quin T Waterbury, Jin Qian, Hualong Zheng, Amanda Dirnberger, Oakley C Olson, Ruth A White, Feijing Wu, Hiroki Kobayashi, Ermanno Malagola, Yosuke Ochiai, Ruhong Tu, Biyun Zheng, Adama Diaby, Harry Nagendra, Jonathan S LaBella, Leah Zamechek, Judith Korner, Ana B Emiliano, Anthony W Ferrante, Emmanuelle Passegué, Timothy C Wang
{"title":"Bone marrow neutrophil density regulates myelopoiesis during obesity and weight loss.","authors":"Quin T Waterbury, Jin Qian, Hualong Zheng, Amanda Dirnberger, Oakley C Olson, Ruth A White, Feijing Wu, Hiroki Kobayashi, Ermanno Malagola, Yosuke Ochiai, Ruhong Tu, Biyun Zheng, Adama Diaby, Harry Nagendra, Jonathan S LaBella, Leah Zamechek, Judith Korner, Ana B Emiliano, Anthony W Ferrante, Emmanuelle Passegué, Timothy C Wang","doi":"10.1084/jem.20242174","DOIUrl":"10.1084/jem.20242174","url":null,"abstract":"<p><p>The bone marrow (BM) is altered in obesity to promote myeloid cell generation, but the mechanisms driving these changes remain unclear. Here, we show that obesogenic stimuli promote adipose tissue macrophages to recruit neutrophils from the BM in mice. Recruitment of BM neutrophils activates hematopoietic stem cells, which produce myeloid cells that accumulate in the circulation and drive inflammation. This recruitment is not resolved by weight loss, leading to sustained myelopoiesis in previously obese mice. Inhibiting neutrophil recruitment out of the BM in obese mice or during weight loss reduces BM myelopoiesis and adipose tissue inflammation, and improves glucose tolerance. In humans with obesity, plasma neutrophil chemokines are increased, correlate with increased insulin resistance, but do not decrease with weight loss. Our results demonstrate that neutrophil recruitment is a key mediator of myelopoiesis during obesity, and targeting this pathway is a potential strategy to improve inflammation during obesity and weight loss.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612172","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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