Immunology最新文献

{"title":"The Roles of T Cells in the Development of Metabolic Dysfunction-Associated Steatohepatitis.","authors":"Zhifa Ge, Qingwei Wu, Chengyu Lv, Qifeng He","doi":"10.1111/imm.13943","DOIUrl":"https://doi.org/10.1111/imm.13943","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous Hydrogen Sulphide Promotes the Ex Vivo Expansion of Haematopoietic Stem Cells by Regulating the Activation of the JAK2/STAT3 Pathway","authors":"Zhiyuan Qiu,&nbsp;Hui Liu,&nbsp;Rongxuan Cao,&nbsp;Shan Wang,&nbsp;Junjun Wang,&nbsp;Wenjun Xu,&nbsp;Rui Zhang,&nbsp;Baohong Wang,&nbsp;Xiaoting Zhang,&nbsp;Qianpeng Li","doi":"10.1111/imm.13935","DOIUrl":"10.1111/imm.13935","url":null,"abstract":"<div>\u0000 \u0000 <p>Haematopoietic stem cell transplantation (HSCT) is one of the key strategies for treating various haematologic malignancies. Although there are haematopoietic stem cells (HSCs) in umbilical cord blood (UCB), the number is limited. Thus, the purpose of this work was to investigate if endogenous hydrogen sulphide (H₂S) could encourage the ex vivo expansion of HSCs produced from UCB (UCB-HSCs). The CD34⁺ and CD34⁺CD38⁻ cells were enriched and separated by immunomagnetic beads. UCB-HSCs were treated with overexpression plasmids of β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulphurtransferase (MPST) and/or stimulated with AG490 (JAK2/STAT3 inhibitor) for 4, 7 or 10 days, respectively. The content of H₂S in cells was detected using its assay kit. The proportion and quantity of CD34⁺, CD34⁺CD38⁻ and CXCR4⁺CD34⁺ cells as well as the ALDH1A1⁺CD34⁺ cells in CD34⁺ cells were detected by flow cytometry. qPCR was used to detect the expression of CD34, CXCR4 and ALDH1A1 in CD34⁺ cells. Western blot was used to detect the activation of the JAK2/STAT3 pathway in CD34⁺ cells. The results showed that endogenous H₂S enhanced the ex vivo expansion of CD34⁺ and CD34⁺CD38⁻ cells, upregulated the expression of CXCR4 and ALDH1A1 during ex vivo expansion of HSCs, and promoted the JAK2/STAT3 pathway in CD34⁺ cells. However, the aforementioned effects of endogenous H₂S were partially reversed by AG490. In conclusion, endogenous H₂S promotes the activation of the JAK2/STAT3 pathway to facilitate the ex vivo expansion of UCB-HSCs.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"175 4","pages":"534-543"},"PeriodicalIF":4.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of IRE1α Alleviates Renal Fibrosis and Downregulates M1 Macrophage Activation via the p38 MAPK Pathway.","authors":"Zichan Guo, Yuting Shen, Xiaxia Yu, Yun Song, Jiyang Zheng, Yuen Zeng, Yazhen Wang, Zhaoyue Fu, Yongli Hou, Dingwen Shi, Liangjian Han, Juan Li, Lihua Chen","doi":"10.1111/imm.13949","DOIUrl":"https://doi.org/10.1111/imm.13949","url":null,"abstract":"<p><p>The enhanced M1 macrophage activation and proportion significantly promote the progression of renal fibrosis in the unilateral ureteral obstruction (UUO) model, while the underlying mechanisms need to be further studied. Here, we examined whether or not endoplasmic reticulum (ER) stress contributed to M1 macrophage activation and the mechanisms in this process. In the UUO mouse model, the proportion of M1 macrophages could be significantly increased in the early renal fibrosis, with the ER stress activated. The inhibitor of ER stress (4-PBA) significantly suppressed the activation of M1 macrophages and alleviated the renal fibrosis in the UUO mouse model. Furthermore, the renal fibrosis could be relieved after the administration of IRE1α inhibitor (4μ8C), with the downregulation of ER stress and M1 macrophage activation. Mechanistically, ER stress-enhanced activation of M1 macrophages was regulated through the IRE1α/XBP1s-p38 MAPK pathway. IRE1α-deficient macrophages could alleviate the renal fibrosis in the UUO mouse model. Thus, our findings suggest that the ER stress pathway regulates M1 macrophage activation in the UUO model, which provides a novel therapeutic approach for renal fibrosis.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application and Perspectives of Immunotherapy in Head and Neck Squamous Cell Carcinoma.","authors":"Zihao Zhang, Xiaohui Meng, Liang Han","doi":"10.1111/imm.13951","DOIUrl":"https://doi.org/10.1111/imm.13951","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma poses grave challenges to clinicians and patients due to its tumour invasiveness and treatment uncertainties. Despite the substantial improvements in conventional treatment modalities such as surgery, chemotherapy and radiotherapy, the recurrence rate and mortality rate of HNSCC remain stubbornly high. Traditionally, the front-line therapy for recurrent/metastatic HNSCC has been the amalgamation of platinum-based drugs/paclitaxel, 5-fluorouracil and cetuximab, yet it only improves the prognosis of some patients, and the overall treatment situation remains severe. Immunotherapy, as an emerging luminary in the domain of cancer treatment, is committed to improving the tumour microenvironment and stimulating the immune system to perform anti-tumour functions. The continuous updates of immune checkpoint inhibitors have also obtained favourable clinical feedback and are expected to overcome the constraints of traditional therapies. This article elaborates on the trends of immunotherapy within the TME and the progress of immunotherapy, aiming to provide new ideas for treatment regimens in the new therapeutic landscape of HNSCC and offer new hope for patients.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Landscape of SPP1⁺ Macrophages Across Tissues and Diseases: A Comprehensive Review.","authors":"Alessandro Palma","doi":"10.1111/imm.13952","DOIUrl":"https://doi.org/10.1111/imm.13952","url":null,"abstract":"<p><p>Macrophages play a critical role in shaping the immune landscape of various diseases, with secreted phosphoprotein 1 (SPP1)-expressing macrophages emerging as a distinct subset implicated in both cancerous and non-cancerous conditions. Leveraging recent advances in single-cell RNA sequencing, numerous studies have identified SPP1⁺ macrophages across diverse pathological contexts, shedding light on their functional heterogeneity. In cancer, SPP1⁺ tumour-associated macrophages contribute to tumour growth, angiogenesis, and immune evasion, often interacting with T cells and stromal components to sustain an immunosuppressive microenvironment. Conversely, in non-cancerous diseases, these macrophages exhibit both profibrotic and disease-promoting properties, depending on the tissue context. This review provides a comprehensive synthesis of the latest findings on SPP1⁺ macrophages, highlighting their roles in tumour progression, immune suppression, tissue remodelling, and fibrosis. By comparing their shared traits and tissue-specific differences, we explore how SPP1⁺ macrophages adapt to distinct microenvironments and influence disease progression. Understanding their conserved and context-dependent functions may open new avenues for therapeutic targeting.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limitation of Deleterious iNOS-Expressing Interstitial Macrophages Is Dependent on Protective IL-1α and IL-17 in Tuberculosis and Existing Obesity","authors":"Vinicius Bottura Apolloni,&nbsp;Rômulo Silva de Oliveira,&nbsp;Ualter Guilherme Cipriano,&nbsp;Giseli Furlan Correa,&nbsp;Ana Flávia Gembre,&nbsp;Thais Fernanda de Campos Fraga-Silva,&nbsp;Leandra Naira Zambelli Ramalho,&nbsp;Diego Luis Costa,&nbsp;Vânia Luiza Deperon Bonato","doi":"10.1111/imm.13947","DOIUrl":"10.1111/imm.13947","url":null,"abstract":"<div>\u0000 \u0000 <p>IL-1α, IL-1β, IFN-γ, IL-17 and the expression of inducible nitric oxide synthase (iNOS) enzyme by macrophages, which generate nitric oxide, are protective against tuberculosis, a disease caused by <i>Mycobacterium tuberculosis</i>. The severity of tuberculosis can be dependent on bacterial load and/or lung immunopathology. Tuberculosis is aggravated by existing comorbidities such as obesity. Obesity induces metabolic dysfunction, meta inflammation and dysbiosis, which increase the prevalence of respiratory diseases and worsen immunopathology. The deficiency of IL-1α (IL-1α^−/−) induces deleterious lung monocytic inflammation and functional activation of the adaptive immune response mediated by T cells during <i>M. tuberculosis</i> infection in non-obese mice. Although iNOS and IFN-γ have been described as protective in experimental tuberculosis, using a model of obesity induced by high-fat diet, we show here an increase in iNOS-expressing interstitial macrophages positively correlated with <i>M. tuberculosis</i> numbers in the lungs of IL-1α^−/− animals, followed by increased frequency of IFN-γ and decreased frequency of IL-17-producing T cells, showing that IFN-γ and iNOS contribute to immunopathology and pulmonary damage. The protective effect of IL-1α, characterised by reduction of lung immunopathology, is dependent on IL-17-producing CD4⁺ cells that negatively regulate iNOS expression on macrophages. Our data provide important implications for tuberculosis with existing obesity that aggravates lung immunopathology associated with an exacerbation of IFN-γ-producing and iNOS-expressing cells.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"175 4","pages":"518-533"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCG Vaccination Reprograms the Function of M-MDSCs and Aggravates Necrotizing Enterocolitis in Neonates","authors":"Yingying Chen,&nbsp;Hui Li,&nbsp;Yongmei Zhang,&nbsp;Fajie Zhao,&nbsp;Jie Zhou","doi":"10.1111/imm.13946","DOIUrl":"10.1111/imm.13946","url":null,"abstract":"<div>\u0000 \u0000 <p>Bacillus Calmette–Guérin (BCG), a live-attenuated vaccine primarily used against tuberculosis (TB), also provides protection against a broad array of antigens or heterologous antigens through the induction of trained immunity (TI). While BCG is generally safe for full-term infants, its application in preterm infants is contentious due to their immature immune systems and heightened susceptibility to adverse effects. Preterm infants, particularly those with low birth weight, are at an elevated risk of severe complications, such as necrotizing enterocolitis (NEC), a life-threatening inflammatory condition of the intestines. NEC is characterised by dysregulated immune responses to microbial colonisation, with myeloid-derived suppressor cells (MDSCs) playing a crucial role in maintaining immune tolerance during early life. This study reveals that BCG vaccination significantly exacerbates NEC severity (<i>p</i> = 0.0048) by enhancing glycolysis and upregulating mTOR-HIF1α signalling in neonatal monocytic MDSCs (M-MDSCs), thereby impairing their immunosuppressive function. Pharmacological or genetic inhibition of mTOR-HIF1α signalling or glycolysis pathways restored M-MDSC function and mitigated NEC severity. These findings complement our previous work on BCG's effects on polymorphonuclear (PMN)-MDSCs and highlight the dual role of BCG: while it provides protective benefits in certain contexts, it may also increase NEC risk in preterm infants by disrupting MDSC-mediated immune tolerance. This study offers critical insights into the mechanisms underlying BCG's off-target effects and underscores the necessity of tailored vaccination strategies for preterm infants to minimise potential risks.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"175 4","pages":"501-517"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR5-Mediated Reprogramming of Regulatory T Cells and Monocytic-Myeloid-Derived Suppressor Cells in Young Dyslipidemic Individuals: A Plausible Therapeutic Approach","authors":"Komal Sagar,&nbsp;Shamima Akhtar,&nbsp;Nikita Kumar,&nbsp;Anil Kumar Tomar,&nbsp;Ambuj Roy,&nbsp;Milind P. Hote,&nbsp;Sudheer Arava,&nbsp;Savita Yadav,&nbsp;Alpana Sharma","doi":"10.1111/imm.13941","DOIUrl":"10.1111/imm.13941","url":null,"abstract":"<div>\u0000 \u0000 <p>Chemokine receptor CCR5 is upregulated in the regulatory T cells (Tregs) and monocytic-myeloid-derived suppressor cells (M-MDSCs) of young dyslipidemic individuals. In this study, we investigated the role of CCR5 in regulating the phenotypic and functional plasticity of Tregs and M-MDSCs during the preclinical phase of atherosclerosis. Inflammatory conditions induce a phenotypic shift in Tregs and M-MDSCs, characterised by enhanced expression of CCR5 and pro-inflammatory cytokines. Tregs from dyslipidemic (DLP) and coronary artery disease (CAD) patients exhibited a mixed Th1/Th17/Treg phenotype, whilst M-MDSCs displayed elevated markers of activation and inflammation. CCR5 inhibition via DAPTA (10⁻⁸ M) restored the immune suppressive phenotype and function of Tregs and M-MDSCs in vitro. Migration of dysfunctional Tregs and M-MDSCs to CCL5 stimulus was also reduced after DAPTA treatment in vitro. In vivo, DAPTA reduced IL-12 expression and elevated IL-10 expression in Tregs and M-MDSCs. Therapeutically targeting CCR5 in Tregs and M-MDSCs of young naive dyslipidemic individuals aids in the dampening of early inflammation and can prevent the progression of atherosclerosis.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"175 4","pages":"467-481"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Canonical Immune Checkpoints: Overexpression of TNFRSF Members 4-1BB and OX-40 Marks T Cells Exhibiting Phenotypic Features of Exhaustion in Cervical Carcinoma","authors":"Jose Manuel Rojas-Diaz,&nbsp;Fabiola Solorzano-Ibarra,&nbsp;Nadia Tatiana Garcia-Barrientos,&nbsp;Ksenia Klimov-Kravtchenko,&nbsp;Jose Alfonso Cruz-Ramos,&nbsp;Marcela Sofia Guitron-Aviña,&nbsp;Pedro Ivan Urciaga-Gutierrez,&nbsp;Pablo Cesar Ortiz-Lazareno,&nbsp;Martha Cecilia Tellez-Bañuelos,&nbsp;Miriam Ruth Bueno-Topete,&nbsp;Jesse Haramati,&nbsp;Susana del Toro-Arreola","doi":"10.1111/imm.13945","DOIUrl":"10.1111/imm.13945","url":null,"abstract":"<div>\u0000 \u0000 <p>T cells are pivotal in combating cancer; however, they can become exhausted during tumour progression, losing their cytotoxic capacity and upregulating inhibitory receptors including PD-1 and TIGIT. While checkpoint blockade has emerged as a potent treatment option for numerous cancers, patient selection, long-term efficacy, and adverse effects still remain an issue. For these reasons, it is important to investigate other pathways that might lead to selective reactivation of the immune system. Co-stimulatory TNFRSF receptors, including 4-1BB and OX-40, have emerged as promising targets for reactivating exhausted T cells. However, their expression on exhausted peripheral and tumour-infiltrating lymphocytes (TILs) is not well characterised, particularly in cervical cancer (CC), which remains the leading cause of gynaecological cancer mortality in low- and middle-income countries. To investigate the expression of these receptors, PBMCs were collected from CC patients and healthy donors, along with TILs from tumour biopsies, and analysed using multiparametric flow cytometry. Our findings revealed an increased population of phenotypically exhausted (PD-1⁺TIGIT⁺) CD4⁺ and CD8⁺ T cells in TILs, and, to a lesser extent, in peripheral blood and from CC patients. These exhausted T cell subsets exhibited selective overexpression of 4-1BB and OX-40 compared to phenotypically non-exhausted cells (PD-1⁻TIGIT⁻). In TILs, 4-1BB was overexpressed 12.7-fold in CD8 cells with the exhausted phenotype, OX-40 was overexpressed 3.3-fold; in CD4 cells with the exhausted phenotype, the overexpression was 7.8× and 3.8× for 4-1BB and OX-40, respectively. CD8 and CD4 T cells that were PD-1 + TIGIT+ 4-1BB+ were 7.3× and 16× more likely to be found in the tumour versus peripheral blood. Additionally, subpopulations of PD-1^high T cells were significantly elevated in the tumour-infiltrating T cells and TIGIT expression was positively associated with PD-1 levels in peripheral patient CD8⁺ and CD4⁺ T cells, potentially indicating an advanced state of exhaustion. These findings suggest that TNFRSF members, especially 4-1BB, may serve as potential immunotherapeutic targets for reinvigorating exhausted T cells in CC.</p>\u0000 </div>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"175 4","pages":"482-500"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibiotic-Induced Dysbiosis of the Gut Microbiota Shifts Host Tryptophan Metabolism and Increases the Susceptibility of Mice to Pulmonary Infection With Pseudomonas aeruginosa","authors":"Camila Bernardo de Brito,&nbsp;Raquel Duque do Nascimento Arifa,&nbsp;Rafael de Oliveira Bezerra,&nbsp;Carlos Eduardo Dias Igídio,&nbsp;Bárbara Maria de Amorim-Santos,&nbsp;Anna Clara Paiva de Menezes Santos,&nbsp;Larissa Mendes Barbosa,&nbsp;João Paulo Pezzini Barbosa,&nbsp;Larissa Marcely Gomes Cassiano,&nbsp;Markus Kohlhoff,&nbsp;Micheli Fagundes,&nbsp;Rafaela Ribeiro Álvares Batista,&nbsp;Celso Martins Queiroz-Junior,&nbsp;Alessandra M. Saliba,&nbsp;Juliana Divina Almeida Raposo,&nbsp;Fernão Castro Braga,&nbsp;Roney Santos Coimbra,&nbsp;Mauro Martins Teixeira,&nbsp;Caio Tavares Fagundes,&nbsp;Danielle G. Souza","doi":"10.1111/imm.13932","DOIUrl":"10.1111/imm.13932","url":null,"abstract":"<p><i>Pseudomonas aeruginosa</i> is an opportunistic bacterium that mainly infects those who have previously been treated with antibiotics. We hypothesised that antibiotic treatment disrupts tryptophan metabolism, leading to increased susceptibility to <i>P. aeruginosa</i> infection. Our results showed that mice receiving antibiotics exhibited intestinal dysbiosis with alterations in host tryptophan metabolism, a higher mortality rate and a higher bacterial load compared to eubiotic mice. In the lungs of the dysbiotic mice, there was an increase in IDO1 (Indoleamine 2,3-dioxygenase 1) activity and an accumulation of kynurenine after infection, and IDO1^−/− mice were resistant to infection after induction of dysbiosis. Importantly, dysbiosis led to increased expression and activation of AHR (Aryl Hydrocarbon Receptor) in an IDO1-dependent manner. Blocking AHR activation in dysbiotic mice resulted in a lower bacterial load. Our data showed that increased AHR activation by kynurenine was associated with decreased phagocytosis of <i>P. aeruginosa</i> by macrophages and neutrophils. In conclusion, our results indicate that dysbiosis resulting from prolonged antimicrobial treatment alters tryptophan metabolism, leading to activation of the IDO1–AHR axis and increasing susceptibility to <i>P. aeruginosa</i> infection. Furthermore, these data suggest that IDO1 or AHR are potential host targets for the prevention of opportunistic infections in patients undergoing antimicrobial therapy.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"175 4","pages":"453-466"},"PeriodicalIF":4.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13932","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}