Nature ImmunologyPub Date : 2025-04-23DOI: 10.1038/s41590-025-02143-5
{"title":"Interferon-β treatment restores myeloid function and reverses immunosuppression in sepsis","authors":"","doi":"10.1038/s41590-025-02143-5","DOIUrl":"https://doi.org/10.1038/s41590-025-02143-5","url":null,"abstract":"Systemic inflammation, such as sepsis, starts with excessive inflammation and is followed by a long-lasting immunosuppressed state. Using single-cell transcriptomics and functional assays, we show that the immunosuppression is driven by impaired monocyte maturation and reduced type I interferon signaling, which could be reversed by treatment with interferon-β.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"32 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862801","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}
Nature ImmunologyPub Date : 2025-04-22DOI: 10.1038/s41590-025-02123-9
Emmanuel L. Gautier
{"title":"Endothelium calls macrophages for destruction","authors":"Emmanuel L. Gautier","doi":"10.1038/s41590-025-02123-9","DOIUrl":"https://doi.org/10.1038/s41590-025-02123-9","url":null,"abstract":"A mouse model of high cholesterol diet and cigarette smoke inhalation provides insights into the roles of macrophage and endothelial dysfunction in the development of abdominal aortic aneurysm.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"37 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857274","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}
Nature ImmunologyPub Date : 2025-04-22DOI: 10.1038/s41590-025-02124-8
Antonio Cembellin-Prieto, Zheng Luo, Heather Kulaga, Nicole Baumgarth
{"title":"B cells modulate lung antiviral inflammatory responses via the neurotransmitter acetylcholine","authors":"Antonio Cembellin-Prieto, Zheng Luo, Heather Kulaga, Nicole Baumgarth","doi":"10.1038/s41590-025-02124-8","DOIUrl":"https://doi.org/10.1038/s41590-025-02124-8","url":null,"abstract":"<p>The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host and yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Sensitive regulators must exist that modulate inflammation, while controlling the infection. In the present study, we identified acetylcholine (ACh)-producing B cells as such early regulators. B cells are the most prevalent ACh-producing leukocyte population in the respiratory tract demonstrated with choline acetyltransferase (ChAT)-green fluorescent protein (GFP) reporter mice, both before and after infection with influenza A virus. Mice lacking ChAT in B cells, disabling their ability to generate ACh (ChatBKO), but not those lacking ChAT in T cells, significantly, selectively and directly suppressed α7-nicotinic-ACh receptor-expressing interstitial, but not alveolar, macrophage activation and their ability to secrete tumor necrosis factor (TNF), while better controlling virus replication at 1 d postinfection. Conversely, TNF blockade via monoclonal antibody treatment increased viral loads at that time. By day 10 of infection, ChatBKO mice showed increased local and systemic inflammation and reduced signs of lung epithelial repair despite similar viral loads and viral clearance. Thus, B cells are key participants of an immediate early regulatory cascade that controls lung tissue damage after viral infection, shifting the balance toward reduced inflammation at the cost of enhanced early viral replication.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"6 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857505","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}
Nature ImmunologyPub Date : 2025-04-22DOI: 10.1038/s41590-025-02132-8
Danya Thayaparan, Takuo Emoto, Aniqa B. Khan, Rickvinder Besla, Homaira Hamidzada, Mahmoud El-Maklizi, Tharini Sivasubramaniyam, Shabana Vohra, Ash Hagerman, Sara Nejat, Charlotte E. Needham-Robbins, Tao Wang, Moritz Lindquist, Steven R. Botts, Stephanie A. Schroer, Masayuki Taniguchi, Taishi Inoue, Katsuhiro Yamanaka, Haotian Cui, Edouard Al-Chami, Hangjun Zhang, Marwan G. Althagafi, Aja Michalski, Joshua J. C. McGrath, Steven P. Cass, David Luong, Yuya Suzuki, Angela Li, Amina Abow, Rachel Heo, Shaun Pacheco, Emily Chen, Felix Chiu, John Byrne, Tomoyuki Furuyashiki, Mansoor Husain, Peter Libby, Kenji Okada, Kathryn L. Howe, Scott P. Heximer, Tomoya Yamashita, Bo Wang, Barry B. Rubin, Myron I. Cybulsky, Joy Roy, Jesse W. Williams, Sarah Q. Crome, Slava Epelman, Ken-ichi Hirata, Martin R. Stampfli, Clinton S. Robbins
{"title":"Endothelial dysfunction drives atherosclerotic plaque macrophage-dependent abdominal aortic aneurysm formation","authors":"Danya Thayaparan, Takuo Emoto, Aniqa B. Khan, Rickvinder Besla, Homaira Hamidzada, Mahmoud El-Maklizi, Tharini Sivasubramaniyam, Shabana Vohra, Ash Hagerman, Sara Nejat, Charlotte E. Needham-Robbins, Tao Wang, Moritz Lindquist, Steven R. Botts, Stephanie A. Schroer, Masayuki Taniguchi, Taishi Inoue, Katsuhiro Yamanaka, Haotian Cui, Edouard Al-Chami, Hangjun Zhang, Marwan G. Althagafi, Aja Michalski, Joshua J. C. McGrath, Steven P. Cass, David Luong, Yuya Suzuki, Angela Li, Amina Abow, Rachel Heo, Shaun Pacheco, Emily Chen, Felix Chiu, John Byrne, Tomoyuki Furuyashiki, Mansoor Husain, Peter Libby, Kenji Okada, Kathryn L. Howe, Scott P. Heximer, Tomoya Yamashita, Bo Wang, Barry B. Rubin, Myron I. Cybulsky, Joy Roy, Jesse W. Williams, Sarah Q. Crome, Slava Epelman, Ken-ichi Hirata, Martin R. Stampfli, Clinton S. Robbins","doi":"10.1038/s41590-025-02132-8","DOIUrl":"https://doi.org/10.1038/s41590-025-02132-8","url":null,"abstract":"<p>Currently there is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms. Using a mouse model that combines cigarette smoke exposure and hypercholesterolemia, we demonstrated that cigarette smoke exacerbated atherosclerosis, leading to elastin fragmentation, aneurysm formation, rupture and death. Arterial injury was driven by macrophages that accumulated within atherosclerotic plaques and exhibited tissue-degrading proteolytic activity in vivo (a process dependent on the endothelial cell-derived macrophage growth factor CSF-1). Single-nucleus RNA sequencing revealed that cigarette smoke-induced endothelial cell dysfunction promoted monocyte recruitment and inflammatory signaling and amplified vascular injury. Furthermore, single-cell transcriptomic analysis identified conserved macrophage responses across mouse and human abdominal aortic aneurysm, including TREM2<sup>+</sup> macrophages, which were key mediators of arterial damage. These findings established atherosclerotic plaque macrophages as critical drivers of aneurysm pathology and provide key insights into the mechanisms underlying aneurysm progression and rupture.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"54 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857508","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}
Nature ImmunologyPub Date : 2025-04-22DOI: 10.1038/s41590-025-02137-3
Bikash Mishra, Mahesh Bachu, Ruoxi Yuan, Claire Wingert, Vidyanath Chaudhary, Caroline Brauner, Richard Bell, Lionel B. Ivashkiv
{"title":"IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms","authors":"Bikash Mishra, Mahesh Bachu, Ruoxi Yuan, Claire Wingert, Vidyanath Chaudhary, Caroline Brauner, Richard Bell, Lionel B. Ivashkiv","doi":"10.1038/s41590-025-02137-3","DOIUrl":"https://doi.org/10.1038/s41590-025-02137-3","url":null,"abstract":"<p>Interleukin-10 (IL-10) is pivotal in suppressing innate immune activation, in large part by suppressing induction of inflammatory genes. Despite decades of research, the molecular mechanisms underlying this inhibition have not been resolved. Here we utilized an integrated epigenomic analysis to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-κB, MAPK–AP-1 and TBK1–IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop. This resulted in suppression of inflammatory NF-κB target genes and near-complete suppression of interferon-stimulated genes. Mechanisms of gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-κB target genes, highlight the role of IRF1 in inflammatory gene expression and describe the suppression of IFN responses by epigenetic mechanisms.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"108 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857204","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}
Nature ImmunologyPub Date : 2025-04-22DOI: 10.1038/s41590-025-02134-6
Mojdeh Shakiba, David A. Tuveson
{"title":"Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer","authors":"Mojdeh Shakiba, David A. Tuveson","doi":"10.1038/s41590-025-02134-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02134-6","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic ‘cold’ tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"41 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857507","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}
Nature ImmunologyPub Date : 2025-04-18DOI: 10.1038/s41590-025-02136-4
Farid Keramati, Guus P. Leijte, Niklas Bruse, Inge Grondman, Ehsan Habibi, Cristian Ruiz-Moreno, Wout Megchelenbrink, Annemieke M. Peters van Ton, Hidde Heesakkers, Manita E. Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter J. van der Velden, Frank W. Preijers, Brigit te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G. Netea, Hendrik G. Stunnenberg, Peter Pickkers, Matthijs Kox
{"title":"Systemic inflammation impairs myelopoiesis and interferon type I responses in humans","authors":"Farid Keramati, Guus P. Leijte, Niklas Bruse, Inge Grondman, Ehsan Habibi, Cristian Ruiz-Moreno, Wout Megchelenbrink, Annemieke M. Peters van Ton, Hidde Heesakkers, Manita E. Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter J. van der Velden, Frank W. Preijers, Brigit te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G. Netea, Hendrik G. Stunnenberg, Peter Pickkers, Matthijs Kox","doi":"10.1038/s41590-025-02136-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02136-4","url":null,"abstract":"<p>Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory <i>CD163</i><sup>+</sup><i>SLC39A8</i><sup>+</sup><i>CALR</i><sup>+</sup> monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"8 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846445","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}
Nature ImmunologyPub Date : 2025-04-18DOI: 10.1038/s41590-025-02133-7
{"title":"Neutrophil senescence drives sexual dimorphism in bladder cancer","authors":"","doi":"10.1038/s41590-025-02133-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02133-7","url":null,"abstract":"We identify an age-related subpopulation of RETNLγ+LCN2+ senescence-like neutrophils (RLSNs) that preferentially accumulate in the tumor microenvironment of male mice and humans. RLSNs exert strong immunosuppressive functions and limit antitumor immunity, and may represent a mechanism to explain sexual dimorphism in bladder cancer.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"108 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846444","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}
Nature ImmunologyPub Date : 2025-04-11DOI: 10.1038/s41590-025-02126-6
Qingchen Zhu, Guiheng Zhang, Ming Cao, Huan Huang, Dan He, Zhongsheng Zang, Jing Xing, Ming Zhan, Siyu Pei, Xiuyu Deng, Juan Li, Guangxun Meng, Jing Xu, Dongfang Dai, Guohong Hu, Mingyue Zheng, Chenli Liu, Jun Qin, Yichuan Xiao
{"title":"Microbiota-shaped neutrophil senescence regulates sexual dimorphism in bladder cancer","authors":"Qingchen Zhu, Guiheng Zhang, Ming Cao, Huan Huang, Dan He, Zhongsheng Zang, Jing Xing, Ming Zhan, Siyu Pei, Xiuyu Deng, Juan Li, Guangxun Meng, Jing Xu, Dongfang Dai, Guohong Hu, Mingyue Zheng, Chenli Liu, Jun Qin, Yichuan Xiao","doi":"10.1038/s41590-025-02126-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02126-6","url":null,"abstract":"<p>Sex disparities have been epidemiologically demonstrated in non-reproductive cancers, yet how the sex-specific intrinsic microbiome orchestrates the immune system to affect these disparities is unclear. Here we identify a subpopulation of RETNLG<sup>+</sup>LCN2<sup>+</sup> senescence-like neutrophils (RLSNs) that preferentially accumulate in the male tumor microenvironment and exert a strong immunosuppressive effect to limit antitumor immunity, resulting in poor prognosis for patients with bladder cancer. This difference in enrichment of RLSNs between sexes can be attributed to intestinal bacterium <i>Alistipes shahii</i>, which preferentially populates in females rather than males. <i>A. shahii</i>-associated metabolite lurasidone directly targets iron sequestrator LCN2 in RLSNs. By freeing Fe<sup>2+</sup>, lurasidone induces ferroptosis, thereby eliminating RLSNs and promoting antitumor immunity in females. In males lacking <i>A. shahii</i> and lurasidone, RLSNs have a survival advantage. Together, these findings demonstrate that a microbiota–lurasidone–LCN2 circuit regulates sexual disparity in bladder cancer and indicates the therapeutic potential of lurasidone for male cancer patients.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"35 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819223","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}
Nature ImmunologyPub Date : 2025-04-10DOI: 10.1038/s41590-025-02141-7
Ryoji Kawakami, Shimon Sakaguchi
{"title":"Treg cells augment self-tolerance during infection","authors":"Ryoji Kawakami, Shimon Sakaguchi","doi":"10.1038/s41590-025-02141-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02141-7","url":null,"abstract":"A fine balance is needed for Treg cells to enable immune responses to pathogens without triggering autoimmunity. Data now show that thymus-derived self-peptide-specific Treg cells suppress conventional T cells during infection, but enable immune responses to pathogen-derived peptides, thus promoting self–nonself discrimination.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"1 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813696","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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