Journal of immunology最新文献_第3页

Correction to: The Receptor for Advanced Glycation End Products Activates the AIM2 Inflammasome in Acute Pancreatitis. 更正：晚期糖基化终产物受体在急性胰腺炎中激活AIM2炎性体。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-22 DOI: 10.1093/jimmun/vkaf261

引用次数: 0

IL-2 mediates human bystander CD8+ T-cell responses to innate immune signals. IL-2介导人旁观者CD8+ t细胞对先天免疫信号的反应。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-22 DOI: 10.1093/jimmun/vkaf196

Tamara Johanna Cornelia Schenk, Martijn Vos, Yannick van Sleen, Jeroen Hoeboer, Debbie van Baarle, Teun Guichelaar

{"title":"IL-2 mediates human bystander CD8+ T-cell responses to innate immune signals.","authors":"Tamara Johanna Cornelia Schenk, Martijn Vos, Yannick van Sleen, Jeroen Hoeboer, Debbie van Baarle, Teun Guichelaar","doi":"10.1093/jimmun/vkaf196","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf196","url":null,"abstract":"In response to an infection, the host T cell compartment develops immunological memory to ensure rapid responses upon re-infection with the same pathogen. However, these memory responses can also modulate immune reactions to unrelated pathogens through bystander activation. Herein, T cells are activated in an antigen-independent manner, often triggered by innate cytokines or Toll-like receptor ligands. To uncover new strategies for modulating immune responses, it is essential to deepen our understanding of this alternative mechanism of T cell activation, particularly in humans. Therefore, we studied the response of human CD8+ T cells to innate bystander stimuli in vitro. Thereby, we measured the induction of activation markers and proliferation using flow cytometry, and depleted or blocked several potential modulatory components to identify mediators of bystander CD8+ T-cell responses. Our study demonstrates that CD8+ T cells can be activated as bystander cells in response to innate stimuli present during a viral infection, including IL-15, IFN-α, and TLR7/8 and 9 agonists (R848 and CpG). Depletion experiments demonstrated that these bystander responses are dependent on monocytes and CD4+ T cells. In addition, we revealed that the bystander responses to the innate stimuli are highly reliant on IL-2 signaling. Altogether, our study underscores the pivotal role of IL-2 in mediating bystander responses of CD8+ T cells to innate stimuli, revealing a novel mechanism of immune response modulation during viral infections.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113149","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}

引用次数: 0

Investigating the activation of the immune response by outer membrane vesicles from Bacteroides fragilis using a human gastrointestinal cell system. 利用人胃肠道细胞系统研究脆弱拟杆菌外膜囊泡对免疫应答的激活作用。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-22 DOI: 10.1093/jimmun/vkaf257

Taylor M Jefferis, Colin Scano, Asha Ashraf, Dinny M Stevens, Amanda Sevcik, Erica Bruce, Leigh Greathouse, Christie M Sayes

{"title":"Investigating the activation of the immune response by outer membrane vesicles from Bacteroides fragilis using a human gastrointestinal cell system.","authors":"Taylor M Jefferis, Colin Scano, Asha Ashraf, Dinny M Stevens, Amanda Sevcik, Erica Bruce, Leigh Greathouse, Christie M Sayes","doi":"10.1093/jimmun/vkaf257","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf257","url":null,"abstract":"Chronic inflammatory diseases are becoming more prevalent in Western countries, yet there is limited research on clinical tools for their cure. Understanding the bacteria in the gastrointestinal tract is crucial for managing these diseases, as pathogenic bacteria can lead to inflammation and cancer, while commensal bacteria help mitigate these harmful effects. For science to continue progressing, there is a need to develop new approach methods that simulate human organ models with high throughput, are cost-effective, and are still precise and accurately representative. Various cells, such as human B lymphocytes (represented by Raji B cells) and human colorectal cells (represented by smooth Caco-2 cells, microfold Caco-2 cells, and HT29-MTX cells), play distinct roles in maintaining intestinal health. In vitro models using these cells help simulate gastrointestinal functions more accurately. We have developed such a model termed \"CHaRM\" (Caco-2, HT29-MTX, and Raji cell Model). Recent studies have shown that introducing different bacterial strains into the gastrointestinal tract increases cytokine activity, with nontoxigenic bacteria (nontoxigenic Bacteroides fragilis) triggering a stronger response than toxigenic bacteria (enterotoxigenic Bacteroides fragilis [ETBF]). While both treatments increased cytokine levels, ETBF did not significantly alter proinflammatory cytokine levels compared to the control. However, PD-L1/B7-H1, a transmembrane protein, decreased with ETBF treatment, as did some growth factor proteins.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113208","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}

引用次数: 0

Non-hematopoietic tryptophan metabolism is a driver of ineffective T cell responses during secondary pulmonary bacterial infection. 非造血色氨酸代谢是继发性肺部细菌感染期间无效T细胞反应的驱动因素。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf197

Lydia M Roberts, Leanne Arakkal, Tara Wehrly, Claire Poore Fonseka, Pavlina Laskova, Benjamin Schwarz, Eric Bohrnsen, Ronald Germain, Catharine M Bosio, Emily Speranza

{"title":"Non-hematopoietic tryptophan metabolism is a driver of ineffective T cell responses during secondary pulmonary bacterial infection.","authors":"Lydia M Roberts, Leanne Arakkal, Tara Wehrly, Claire Poore Fonseka, Pavlina Laskova, Benjamin Schwarz, Eric Bohrnsen, Ronald Germain, Catharine M Bosio, Emily Speranza","doi":"10.1093/jimmun/vkaf197","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf197","url":null,"abstract":"Pulmonary infections often fail to produce long-lived immune memory and the underlying mechanism(s) for this are unclear. Given the complex interactions between cells within the lung, we predicted intrinsic and extrinsic factors contribute to development of poor memory immune responses. To identify these factors, we used a multiomics approach to determine host-driven responses that undermine or support development of effective immune responses in two mouse models of pulmonary bacterial infections. Single cell RNA analysis and spatial imaging of the lung revealed that, in contrast to Bordetella pertussis driven immunity, subpar responses following Francisella tularensis infection were associated with the inability of T cells to readily proliferate upon re-challenge and absence of formation of iBALT. Further, we also identified that these features were partially a consequence of IFN-γ driven reprogramming of endothelial cells resulting in expression of IDO1 and dysregulated tryptophan metabolism. Interestingly, IDO1 expression and imbalanced tryptophan persisted even after clearance of the primary infection. The importance of expression of IDO1 was confirmed using IDO1 knock out mice. Specifically, these animals could withstand higher doses of the initial infection and developed significantly larger pools of functional T cells compared to wild type controls. Together, these results demonstrate critical crosstalk among cells in the lung that influences spatial organization of immune cells which affects the ability to develop effective memory immune responses against secondary bacterial infection. Our data also underscores the challenge of utilizing a live vaccine strategy against tularemia and the necessity for identifying novel, acellular vaccine candidates.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091976","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}

引用次数: 0

DOT1L-mediated H3K79me2 directs B-cell repertoire establishment, marginal zone development, and germinal center function. dot1l介导的H3K79me2指导b细胞库的建立、边缘区发育和生发中心功能。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf243

Liam C Kealy, Brendan E Russ, Stephen J Turner, Elias Hobeika, Kim L Good-Jacobson

{"title":"DOT1L-mediated H3K79me2 directs B-cell repertoire establishment, marginal zone development, and germinal center function.","authors":"Liam C Kealy, Brendan E Russ, Stephen J Turner, Elias Hobeika, Kim L Good-Jacobson","doi":"10.1093/jimmun/vkaf243","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf243","url":null,"abstract":"Disruptor of telomeric silencing 1-like (DOT1L) is an epigenetic regulator that promotes gene expression by methylating lysine 79 on histone H3 and recruits transcription factors to gene targets. DOT1L is also an oncogenic driver in cancers that affect developing lymphocytes, yet how DOT1L activity regulates B-cell maturation remains poorly defined. Here, we use deep-sequencing and conditional knockout models to elucidate gene targets of H3K79me2, and the mechanistic contribution of DOT1L, during key stages of murine B-cell development. In the bone marrow, Dot1l was upregulated in pro B cells. Deep sequencing revealed that H3K79me2 accumulated during maturation. The genomic distribution of H3K79me2 peaks indicated that DOT1L regulates transcription and the cell cycle across different stages of B-cell development. As such, DOT1L was found to be essential for pre B-cell expansion, leading to a significant decrease in pre B cells in the absence of DOT1L and a skewing of the B-cell receptor repertoire to favor proximal VH usage. In addition to the effective generation of a diverse B-cell pool, DOT1L was also required to establish the marginal zone (MZ) B-cell gene expression program. Attenuation of MZ B cells and a bottlenecking at the pre-MZ B-cell stage in Dot1L-deficient mice correlated to H3K79me2 peaks at key MZ-regulatory genes such as Lfng and Dock10 in developing B cells. In contrast, Dot1l was reexpressed in germinal center (GC) B cells postimmunization to deposit H3K79me2 at key GC B-cell gene loci during GC differentiation. Together, these data demonstrate a vital role for DOT1L during B-cell lymphopoiesis, MZ B-cell generation, and GC B-cell biology.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091860","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}

引用次数: 0

An early burst of cytokine production before the first cell division influences CD8 T cell differentiation. 在第一次细胞分裂之前，细胞因子产生的早期爆发影响CD8 T细胞的分化。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf239

Shannon M Kahan, Jennifer T Ingram, Robert S Welner, Casey T Weaver, Laurie E Harrington, Allan J Zajac

{"title":"An early burst of cytokine production before the first cell division influences CD8 T cell differentiation.","authors":"Shannon M Kahan, Jennifer T Ingram, Robert S Welner, Casey T Weaver, Laurie E Harrington, Allan J Zajac","doi":"10.1093/jimmun/vkaf239","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf239","url":null,"abstract":"The differentiation of CD8 T cells into effector and memory populations is guided by a combination of antigenic, costimulatory, and cytokine signals. Here we show that, within 24 h of activating naïve CD8 T cells, populations emerge with divergent patterns of interleukin (IL)-2 and interferon (IFN)-γ synthesis. This rapid, dynamic, and heterogeneous burst of cytokine production manifests with every CD8 T cell specificity analyzed, is apparent in vivo and in vitro, and occurs prior to the first cell division. Nevertheless, how the intrinsic manufacture of distinct cytokines forecasts and influences the properties and fates of the producer cell itself are not well defined. We demonstrate that the initial cell intrinsic synthesis of IL-2 attenuates IL-2-dependent STAT5 signaling, but that this is not due to differences in the surface expression of the IL-2 receptor complex. The functionally discrete subsets are transcriptionally distinct and display differences in the expression of hallmark effector and memory associated genes. Using cytokine reporter systems, we reveal that these early functional differences are consequential for establishing fate biases and directing the gain of effector and memory T cell properties. The bifurcation between the abilities of IL-2-producing and non-producing subsets to elaborate STAT5 signaling is consistent with a model in which non-IL-2-producing CD8 T cells are more receptive to extrinsic IL-2 signals and preferentially contribute to the early surge of effector formation. Despite this, both IL-2-producing and non-producing CD8 T cells can go on to acquire memory traits, indicating that there is developmental diversity within each cytokine producing subset.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113524","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}

引用次数: 0

Development of a murine tumor-infiltrating lymphocyte therapy model for cholangiocarcinoma. 小鼠肿瘤浸润淋巴细胞治疗胆管癌模型的建立。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf242

Megen C Wittling, Frances J Bennett, Emilie A K Warren, Kailey M Oppat, Megan M Wyatt, Jacklyn N Hammons, Yuan Liu, Shishir K Maithel, Chrystal M Paulos, Gregory B Lesinski

{"title":"Development of a murine tumor-infiltrating lymphocyte therapy model for cholangiocarcinoma.","authors":"Megen C Wittling, Frances J Bennett, Emilie A K Warren, Kailey M Oppat, Megan M Wyatt, Jacklyn N Hammons, Yuan Liu, Shishir K Maithel, Chrystal M Paulos, Gregory B Lesinski","doi":"10.1093/jimmun/vkaf242","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf242","url":null,"abstract":"Tumor-infiltrating lymphocyte (TIL) therapy is a promising approach, earning U.S. Food and Drug Administration approval in patients with anti-PD-1-resistant melanoma. Extending TIL therapy to patients with cholangiocarcinoma (CCA), an aggressive and largely immune-refractory cancer, is an emerging area of interest. However, cost and manufacturing complexity constrain clinical scalability of TIL therapy for CCA, underscoring the need for a murine model to optimize efficacy. Here, we established a novel orthotopic model of TIL therapy for CCA and tested a new ex vivo expansion strategy. We first characterized the immune landscape of orthotopic CCA and then compared 2 TIL expansion methods: (1) a conventional protocol using CD3 agonist stimulation (CD3 TILs) and (2) a tumor antigen-based protocol using irradiated autologous CCA cells to enrich for tumor-reactive TILs (Tumor Ag TILs). Tumor Ag TILs displayed superior tumor lysis in vitro compared to CD3 TILs. While both TIL products engrafted in vivo, Tumor Ag TILs showed enhanced persistence. Despite this, monotherapy with either TIL product alone had only a modest impact on tumor growth rate, and infused cells had upregulation of inhibitory checkpoint receptors, including PD-1. Further investigations demonstrated that the in vivo antitumor efficacy of both Tumor Ag TILs and CD3 TILs was enhanced when combined with PD-L1 inhibitor therapy. Altogether, our study establishes a preclinical platform for modeling CCA TIL therapy, identifies a rational combination strategy that potentiates TIL efficacy, and provides the field with a foundation to advance adoptive T-cell transfer development for CCA and related solid tumors.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091841","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}

引用次数: 0

Transcriptional states of lung cancer microenvironment reveal macrophage subtype dynamics linked to disease progression. 肺癌微环境的转录状态揭示了与疾病进展相关的巨噬细胞亚型动态

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf253

Duygu Keremitçi, Özlem Tuna, Aissa Houdjedj, Hilal Kazan, Yasin Kaymaz

{"title":"Transcriptional states of lung cancer microenvironment reveal macrophage subtype dynamics linked to disease progression.","authors":"Duygu Keremitçi, Özlem Tuna, Aissa Houdjedj, Hilal Kazan, Yasin Kaymaz","doi":"10.1093/jimmun/vkaf253","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf253","url":null,"abstract":"The tumor microenvironment (TME) plays a pivotal role in shaping immune responses and therapeutic outcomes in lung cancer, yet the diversity and functional specialization of tumor-associated macrophages (TAMs) remain poorly resolved. Here, we present a refined classification of TAM subtypes across large cohorts of cancer datasets using integrative analysis of single-cell RNA sequencing, spatial transcriptomics, and clinical datasets from lung adenocarcinoma and lung squamous cell carcinoma. By combining cell-based gene scoring with hierarchical classification, we defined 7 macrophage subtypes-each with distinct transcriptional programs and abundances. Notably, lipid-associated TAMs expand with disease progression and exhibit immunosuppressive and protumorigenic features, whereas tissue-resident macrophages decline. Spatial and survival analyses reveal that an increased lipid-associated to tissue-resident TAM ratio correlates with advanced disease and poor prognosis. Given that spatial transcriptomic assays rely on deconvolution techniques to infer cell type compositions, accurate gene expression signatures are essential, especially for fine-grained subpopulations of TAMs. Our refined subtype-specific signatures address this bottleneck and enhance the resolution of spatial mapping efforts. These findings offer new insights into macrophage heterogeneity and highlight lipid-associated TAMs as potential biomarkers and therapeutic targets in lung cancer.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091944","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}

引用次数: 0

UTY coordinates with UTX to repress NK cell development and maturation in males. UTY与UTX协同抑制雄性NK细胞的发育和成熟。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf248

Pei Huang, Hongchen Wang, Xiao Guan, Rongxi Pu, Yu Wu, He Huang, Kangyu Yao, Die Hu, Simin Zhou, Liang Song, Meng Meng, Qinghua Bi, Yang Wang, Zhifeng Zhong, Xinyi Liao, Huaping Dong, Qintao Zhang, Jijian Zhang, Chunyan Sun, Xiaoxu Li, Jiaqi Zhao, Hongming Miao, Peng Li, Jiaxin Xie, Youcai Deng

{"title":"UTY coordinates with UTX to repress NK cell development and maturation in males.","authors":"Pei Huang, Hongchen Wang, Xiao Guan, Rongxi Pu, Yu Wu, He Huang, Kangyu Yao, Die Hu, Simin Zhou, Liang Song, Meng Meng, Qinghua Bi, Yang Wang, Zhifeng Zhong, Xinyi Liao, Huaping Dong, Qintao Zhang, Jijian Zhang, Chunyan Sun, Xiaoxu Li, Jiaqi Zhao, Hongming Miao, Peng Li, Jiaxin Xie, Youcai Deng","doi":"10.1093/jimmun/vkaf248","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf248","url":null,"abstract":"Natural killer (NK) cells are pivotal innate lymphoid cells in anti-tumor immunity. However, the contribution of the Y chromosome-encoded epigenetic regulator UTY (also known as KDM6C) to male NK cell development and effector function remains poorly characterized. Here, we demonstrated that conditional deletion of UTY in NK cells (Ncr1-iCre) in male mice led to a statistically significant but modest increase in total NK cell numbers (P < 0.05) and an elevated frequency of terminally differentiated CD27-CD11b+ subset in the spleen. Strikingly, UTY-deficient NK cells displayed impaired cytotoxic function, with significantly reduced granzyme B expression (P < 0.05) and attenuated control of B16F10 melanoma pulmonary metastases in vivo (P < 0.05). Importantly, combined UTX-UTY deficiency exacerbated these phenotypes, causing further increase in NK cell abundance, and decline in CD27+CD11b+ subset proportions and granzyme B expression level compared with UTX single knockout in male mice. RNA-sequencing combined with qRT-PCR validation uncovered significant downregulation of key genes involved in NK cell maturation (Cd27), cytotoxicity (Gzmb), survival (Bax, Casp3) and transcriptional regulation (Socs3, Tcf7, Fos) in UTY-deficient NK cells. Notably, dual UTX-UTY depletion synergistically repressed Casp3 expression, potentially contributing to the altered NK cell abundance (P < 0.05). These findings establish UTY as a sex-specific epigenetic modulator that restricts NK cell maturation while promoting cytotoxic function. Our data further reveal a cooperative role for UTY and UTX in orchestrating NK cell development via transcriptional regulation.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091925","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}

引用次数: 0

Dimethyl itaconate attenuates IL-1-induced IVIG-resistant inflammation in a coronary artery cell model of Kawasaki disease. 衣康酸二甲酯减轻川崎病冠状动脉细胞模型中il -1诱导的ivig抵抗性炎症

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-16 DOI: 10.1093/jimmun/vkaf245

Ikuyo Ito, Shokei Murakami, Takashi Inoue, Shuichi Ito, Jun Abe, Kenichiro Motomura, Hideaki Morita, Kenji Matsumoto, Akio Matsuda

{"title":"Dimethyl itaconate attenuates IL-1-induced IVIG-resistant inflammation in a coronary artery cell model of Kawasaki disease.","authors":"Ikuyo Ito, Shokei Murakami, Takashi Inoue, Shuichi Ito, Jun Abe, Kenichiro Motomura, Hideaki Morita, Kenji Matsumoto, Akio Matsuda","doi":"10.1093/jimmun/vkaf245","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf245","url":null,"abstract":"Kawasaki disease (KD) is the most common childhood vasculitis. Approximately 25% of KD patients are refractory to standard intravenous immunoglobulin (IVIG) therapy and frequently develop coronary artery lesions (CAL) that result in long-term complications. Transcriptome studies utilizing blood cells from KD patients and reported animal model studies had identified interleukin (IL)-1β as a crucial component of an essential immune pathway in the formation of CAL. We previously reported that high-dose immunoglobulin G (IgG) treatment completely inhibited tumor necrosis factor (TNF)-α-stimulated inflammatory responses in an in vitro human coronary artery endothelial cells (HCAECs) model. Here, we show that IL-1β, but not TNF-α, stimulation markedly induced nuclear protein expression of NF-kappa-B inhibitor zeta (IκBζ) in HCAECs. It is of particular significance that IL-1β-induced IκBζ expression is entirely refractory to high-dose IgG treatment. Therefore, IκBζ may be a critical factor in the IVIG-resistant vascular inflammatory responses in severe KD. Itaconate is a Krebs cycle-derived metabolite with several immunomodulatory effects. Dimethyl itaconate (DI), a membrane-permeable derivative of itaconate, can significantly suppress IL-1β-induced IκBζ expression in HCAECs. DI is an analog of dimethyl fumarate (DMF), which is already in clinical use for some diseases. Like DI, DMF suppressed IL-1β-induced IκBζ expression and subsequent production of inflammatory cytokines, including IL-6 and G-CSF. This study identified IκBζ as an essential inflammatory factor in IVIG-resistant inflammatory responses in HCAECs. Immunomodulatory substances, such as DI and/or DMF, may be therapeutically exploited as a novel drug to alleviate inflammation in severe IVIG-resistant KD patients.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091852","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}

引用次数: 0