Cellular &Molecular Immunology最新文献

{"title":"NLRP3 inflammasome in neuroinflammation and central nervous system diseases","authors":"Wen Xu, Yi Huang, Rongbin Zhou","doi":"10.1038/s41423-025-01275-w","DOIUrl":"10.1038/s41423-025-01275-w","url":null,"abstract":"Neuroinflammation plays an important role in the pathogenesis of various central nervous system (CNS) diseases. The NLRP3 inflammasome is an important intracellular multiprotein complex composed of the innate immune receptor NLRP3, the adaptor protein ASC, and the protease caspase-1. The activation of the NLRP3 inflammasome can induce pyroptosis and the release of the proinflammatory cytokines IL-1β and IL-18, thus playing a central role in immune and inflammatory responses. Recent studies have revealed that the NLRP3 inflammasome is activated in the brain to induce neuroinflammation, leading to further neuronal damage and functional impairment, and contributes to the pathological process of various neurological diseases, such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and stroke. In this review, we summarize the important role of the NLRP3 inflammasome in the pathogenesis of neuroinflammation and the pathological course of CNS diseases and discuss potential approaches to target the NLRP3 inflammasome for the treatment of CNS diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"341-355"},"PeriodicalIF":21.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01275-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613726","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":"Fueling defense: PPARα enhances macrophage inflammatory responses","authors":"Marten A. Hoeksema","doi":"10.1038/s41423-025-01265-y","DOIUrl":"10.1038/s41423-025-01265-y","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"461-462"},"PeriodicalIF":21.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603799","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":"On the origin of neutrophils","authors":"Leo Koenderman, Kiki Tesselaar, Nienke Vrisekoop","doi":"10.1038/s41423-025-01270-1","DOIUrl":"10.1038/s41423-025-01270-1","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"459-460"},"PeriodicalIF":21.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522763","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":"Inflammation-triggered Gli1+ stem cells engage with extracellular vesicles to prime aberrant neutrophils to exacerbate periodontal immunopathology","authors":"Xin-Yue Cai, Chen-Xi Zheng, Hao Guo, Si-Yuan Fan, Xiao-Yao Huang, Ji Chen, Jie-Xi Liu, Yu-Ru Gao, An-Qi Liu, Jia-Ning Liu, Xiao-Hui Zhang, Chao Ma, Hao Wang, Fei Fu, Peng Peng, Hao-Kun Xu, Bing-Dong Sui, Kun Xuan, Yan Jin","doi":"10.1038/s41423-025-01271-0","DOIUrl":"10.1038/s41423-025-01271-0","url":null,"abstract":"Periodontitis is a prevalent and progressive detrimental disease characterized by chronic inflammation, and the immunopathological mechanisms are not yet fully understood. Mesenchymal stem cells (MSCs) play crucial roles as immunoregulators and maintain tissue homeostasis and regeneration, but their in vivo function in immunopathology and periodontal tissue deterioration is still unclear. Here, we utilized multiple transgenic mouse models to specifically mark, ablate and modulate Gli1+ cells, a critical and representative subset of MSCs in the periodontium, to explore their specific role in periodontal immunopathology. We revealed that Gli1+ cells, upon challenge with an inflammatory microenvironment, significantly induce rapid trafficking and aberrant activation of neutrophils, thus exacerbating alveolar bone destruction. Mechanistically, extracellular vesicles (EVs) released by Gli1+ cells act as crucial immune regulators in periodontal tissue, mediating the recruitment and activation of neutrophils through increased neutrophil generation of reactive oxygen species and stimulation of nuclear factor kappa-B signaling. Furthermore, we discovered that CXC motif chemokine ligand 1 (CXCL1) is exposed on the surface of EVs derived from inflammation-challenged Gli1+ cells to prime aberrant neutrophils via the CXCL1-CXC motif chemokine receptor 2 (CXCR2) axis. Importantly, specific inhibition of EV release from Gli1+ cells or pharmacological therapy with GANT61 ameliorates periodontal inflammation and alveolar bone loss. Collectively, our findings identify previously unrecognized roles of Gli1+ cells in orchestrating infiltration and promoting aberrant activation of neutrophils under inflammation, which provides pathological insights and potential therapeutic targets for periodontitis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"371-389"},"PeriodicalIF":21.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522760","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":"Targeting macrophage polarization by inhibiting Pim2 alleviates inflammatory arthritis via metabolic reprogramming","authors":"Xiaojun Xu, Peitao Xu, Guozhen Shen, Xiaoshuai Peng, Zhidong Liu, Chaoqiang Chen, Wenhui Yu, Zepeng Su, Jiajie Lin, Guan Zheng, Guiwen Ye, Peng Wang, Zhongyu Xie, Yanfeng Wu, Huiyong Shen, Jinteng Li","doi":"10.1038/s41423-025-01268-9","DOIUrl":"10.1038/s41423-025-01268-9","url":null,"abstract":"Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis. Moreover, although previous studies have reported that the proviral integration of Moloney virus 2 (Pim2) kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells, its role in inflammatory arthritis remains unclear. In this study, we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization. Specifically, Pim2 directly phosphorylates PGK1-S203, PDHA1-S300, and PFKFB2-S466, thereby promoting glycolytic reprogramming. Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collagen-induced arthritis (CIA) model mice. Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization. Through molecular docking and dynamic simulation, bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization, thereby mitigating the progression of inflammatory arthritis. For targeted treatment, neutrophil membrane-coated bexarotene (Bex)-loaded PLGA-based nanoparticles (NM@NP-Bex) were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages, and these nanoparticles (NPs) exhibited superior therapeutic effects with fewer side effects. Taken together, the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance. NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"418-436"},"PeriodicalIF":21.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01268-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499584","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":"Gut-derived macrophages link intestinal damage to brain injury after cardiac arrest through TREM1 signaling","authors":"Yuan Chang, Jiancong Chen, Yuqin Peng, Kunxue Zhang, Yuzhen Zhang, Xiaolin Zhao, Di Wang, Lei Li, Juan Zhu, Kewei Liu, Zhentong Li, Suyue Pan, Kaibin Huang","doi":"10.1038/s41423-025-01263-0","DOIUrl":"10.1038/s41423-025-01263-0","url":null,"abstract":"Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation triggered by infiltrating macrophages plays a pivotal role. Here, we seek to elucidate the origin of macrophages infiltrating the brain and their mechanism of action after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Wild-type or photoconvertible Cd68-Cre:R26-LSL-KikGR mice were subjected to 10-min CA/CPR, and the migration of gut-derived macrophages into brain was assessed. Transcriptome sequencing was performed to identify the key proinflammatory signal of macrophages infiltrating the brain, triggering receptor expressed on myeloid cells 1 (TREM1). Upon drug intervention, the effects of TREM1 on post-CA/CPR brain injury were further evaluated. 16S rRNA sequencing was used to detect gut dysbiosis after CA/CPR. Through photoconversion experiments, we found that small intestine-derived macrophages infiltrated the brain and played a crucial role in triggering secondary brain injury after CA/CPR. The infiltrating peripheral macrophages showed upregulated TREM1 levels, and we further revealed the crucial role of gut-derived TREM1+ macrophages in post-CA/CPR brain injury through a drug intervention targeting TREM1. Moreover, a close correlation between upregulated TREM1 expression and poor neurological outcomes was observed in CA survivors. Mechanistically, CA/CPR caused a substantial expansion of Enterobacter at the early stage, which ignited intestinal TREM1 signaling via the activation of Toll-like receptor 4 on macrophages through the release of lipopolysaccharide. Our findings reveal essential crosstalk between the gut and brain after CA/CPR and underscore the potential of targeting TREM1+ small intestine-derived macrophages as a novel therapeutic strategy for mitigating post-CA/CPR brain injury.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"437-455"},"PeriodicalIF":21.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472375","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":"β-hydroxybutyrylation and O-GlcNAc modifications of STAT1 modulate antiviral defense in aging","authors":"Yibo Zuo, Qin Wang, Wanying Tian, Zhijin Zheng, Wei He, Renxia Zhang, Qian Zhao, Ying Miao, Yukang Yuan, Jun wang, Hui Zheng","doi":"10.1038/s41423-025-01266-x","DOIUrl":"10.1038/s41423-025-01266-x","url":null,"abstract":"Aging changes the protein activity status to affect the body’s functions. However, how aging regulates protein posttranslational modifications (PTMs) to modulate the antiviral defense ability of the body remains unclear. Here, we found that aging promotes STAT1 β-hydroxybutyrylation (Kbhb) at Lys592, which inhibits the interaction between STAT1 and type-I interferon (IFN-I) receptor 2 (IFNAR2), thereby attenuating IFN-I-mediated antiviral defense activity. Additionally, we discovered that a small molecule from a plant source, hydroxy camptothecine, can effectively reduce the level of STAT1 Kbhb, thus increasing antiviral defense ability in vivo. Further studies revealed that STAT1 O-GlcNAc modifications at Thr699 block CBP-induced STAT1 Kbhb. Importantly, fructose can improve IFN-I antiviral defense activity by orchestrating STAT1 O-GlcNAc and Kbhb modifications. This study reveals the significance of the switch between STAT1 Kbhb and O-GlcNAc modifications in regulating IFN-I antiviral immunity during aging and provides potential strategies to improve the body’s antiviral defense ability in elderly individuals.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"403-417"},"PeriodicalIF":21.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467066","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":"Type 2 immunity in allergic diseases","authors":"Ismail Ogulur, Yasutaka Mitamura, Duygu Yazici, Yagiz Pat, Sena Ardicli, Manru Li, Paolo D’Avino, Carina Beha, Huseyn Babayev, Bingjie Zhao, Can Zeyneloglu, Oliva Giannelli Viscardi, Ozge Ardicli, Ayca Kiykim, Asuncion Garcia-Sanchez, Juan-Felipe Lopez, Li-li Shi, Minglin Yang, Stephan R. Schneider, Stephen Skolnick, Raja Dhir, Urszula Radzikowska, Abhijeet J. Kulkarni, Manal Bel Imam, Willem van de Veen, Milena Sokolowska, Mar Martin-Fontecha, Oscar Palomares, Kari C. Nadeau, Mubeccel Akdis, Cezmi A. Akdis","doi":"10.1038/s41423-025-01261-2","DOIUrl":"10.1038/s41423-025-01261-2","url":null,"abstract":"Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"211-242"},"PeriodicalIF":21.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01261-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439559","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":"Antigen-presenting innate lymphoid cells induced by BCG vaccination promote a respiratory antiviral immune response through the skin‒lung axis","authors":"Dou Yu, Xintong Gao, Fei Shao, Zhen Liu, Aoyi Liu, Min Zhao, Zhuozhou Tang, Yude Guan, Shuo Wang","doi":"10.1038/s41423-025-01267-w","DOIUrl":"10.1038/s41423-025-01267-w","url":null,"abstract":"The route of vaccine administration is associated with various immune outcomes, and the relationship between the route of administration and broad protection against heterologous pathogens remains unclear. Here, we found that subcutaneous vaccination with Bacillus Calmette-Guérin (BCG) promotes respiratory influenza clearance and T-cell responses. Group 1 innate lymphoid cells (ILC1s) express MHCII molecules and engage in antigen processing and presentation after BCG vaccination. During influenza virus infection, ILC1s in the lungs of BCG-vaccinated mice can present influenza virus antigens and prime Th1 cells. After subcutaneous vaccination with BCG, MHCII+ ILC1s migrate from the skin to the lungs and play an antigen-presenting role in influenza infection. Both the BCG and the BCG component lipomannan can induce MHCII expression and skin-to-lung migration of ILC1s via TLR2 signaling. Our study revealed an important regulatory mechanism by which subcutaneous vaccination with BCG promotes respiratory antiviral immune responses via the skin‒lung axis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"390-402"},"PeriodicalIF":21.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439541","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":"Uncovering two neutrophil-committed progenitors that immediately precede promyelocytes during human neutropoiesis","authors":"Ilaria Signoretto, Federica Calzetti, Giulia Finotti, Silvia Lonardi, Camillo Balanzin, Francisco Bianchetto-Aguilera, Sara Gasperini, Elisa Gardiman, Monica Castellucci, Anna Russignan, Massimiliano Bonifacio, Antonio Sica, William Vermi, Cristina Tecchio, Patrizia Scapini, Nicola Tamassia, Marco A. Cassatella","doi":"10.1038/s41423-025-01259-w","DOIUrl":"10.1038/s41423-025-01259-w","url":null,"abstract":"Technological advances have greatly improved our knowledge of myelopoiesis, for example, with the discovery of granulocyte‒monocyte‒dendritic cell (DC) progenitors (GMDPs), monocyte‒DC progenitors (MDPs), common DC progenitors (CDPs) and common monocyte progenitors (cMoPs) on the basis of flow cytometry approaches. Concomitantly, some progress has been made in characterizing the very early phases of human neutropoiesis with the description of novel CD66b+ progenitors, including eNePs, PMs w/o eNePs, ProNeus, and PreNeus. More recently, we identified four SSCloLin-CD66b-CD45dimCD34+/CD34dim/-CD64dimCD115- cells as the earliest precursors specifically committed to the neutrophil lineage present in human bone marrow (BM), which we called neutrophil-committed progenitors (NCPs, from NCP1s to NCP4s). In this study, we report the isolation and characterization of two new SSChiCD66b-CD64dimCD115-NCPs that, by phenotypic, transcriptomic, maturation and immunohistochemistry properties, as well as by flow cytometric side-scattered light (SSC), stand after NCP4s but precede promyelocytes during the neutropoiesis cascade. Similar to SSCloCD45RA+NCP2s/NCP3s and SSCloCD45RA-NCP1s/NCP4s, these cells exhibit phenotypic differences in CD45RA expression levels and, therefore, were named SSChiCD45RA+NCP5s and SSChiCD45RA-NCP6s. Moreover, NCP5s were more immature than NCP6s, as determined by cell differentiation and proliferative potential, as well as by transcriptomic and phenotypical features. Finally, by examining whether NCPs and all other CD66b+ neutrophil precursors are altered in representative hematological malignancies, we found that, in patients with chronic-phase chronic myeloid leukemia (CP-CML), but not with systemic mastocytosis (SM), there is an increased frequency of BM NCP4s, NCP6s, and all downstream CD45RA-negative neutrophil progenitors, suggesting their expansion in CML pathogenesis. Taken together, our data advance our knowledge of human neutropoiesis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"316-329"},"PeriodicalIF":21.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01259-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406019","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}