Ethnopharmacological treatments have shown beneficial effects in the clinical practice of autoimmune disorders. However, the underlying mechanism of immunomodulatory effects remains challenging, given the complicate composition of herbal medicines. Here, we developed an immunological approach to interrogate the T helper cell response. Through data mining we hypothesized that Chinese medicine formula, Yu-Ping-Feng (YPF) might be a promising candidate for treating primary Sjögren's syndrome (pSS), a common autoimmune disease manifested by exocrine gland dysfunction. We took advantage of a mouse model of experimental Sjögren's syndrome (ESS) that we previously established for YPF formula treatment. YPF therapy ameliorated the ESS pathology in mice with active disease, showing improved salivary function and decreased serum levels of autoantibodies. Phenotypic analysis suggested that both effector T and B cells were significantly suppressed. Using co-culture assay and adoptive transfer models, we demonstrated that YPF formula directly restrained effector/memory T cell expansion and differentiation into Th17 and T follicular helper (Tfh) cells, the key subsets in ESS pathogenesis. Importantly, we recruited 20 pSS patients and conducted a pilot study of 8-week therapy of YPF formula. YPF treatment effectively improved fatigue symptoms, exocrine gland functions and reduced serum IgG/IgA levels, while effector T and B cell subsets were significantly decreased. There was a trend of reduction on disease activity, but not statistically significant. Together, our findings suggested a novel approach to assess the immunomodulatory effects of YPF formula, which may be favorable for patients with autoimmune disorders.
在自身免疫性疾病的临床实践中,民族药理学疗法已显示出有益的效果。然而,由于中药成分复杂,免疫调节作用的基本机制仍具有挑战性。在此,我们开发了一种免疫学方法来研究 T 辅助细胞的反应。通过数据挖掘,我们推测中药配方玉屏风散可能是治疗原发性斯约格伦综合征(pSS)的候选药物,这是一种常见的自身免疫性疾病,表现为外分泌腺功能障碍。我们利用之前建立的实验性斯约格伦综合征(ESS)小鼠模型进行了叶黄素配方治疗。YPF疗法改善了活动期小鼠的ESS病理学,显示出唾液功能的改善和自身抗体血清水平的降低。表型分析表明,效应 T 细胞和 B 细胞均受到明显抑制。通过共培养试验和收养性转移模型,我们证明了 YPF 配方能直接抑制效应T细胞/记忆T细胞的扩增和分化为 Th17 和 T 滤泡辅助细胞(Tfh),而这两种细胞正是ESS 发病机制中的关键亚群。重要的是,我们招募了20名ESS患者,进行了为期8周的YPF配方治疗试验研究。YPF治疗有效改善了疲劳症状和外分泌腺功能,降低了血清IgG/IgA水平,同时效应T细胞和B细胞亚群明显减少。疾病活动有减少趋势,但无统计学意义。总之,我们的研究结果为评估 YPF 配方的免疫调节作用提供了一种新方法,它可能对自身免疫性疾病患者有利。
{"title":"Immunomodulatory Effects of Yu-Ping-Feng Formula on Primary Sjögren's Syndrome: Interrogating the T Cell Response.","authors":"Sulan Yu, Xinyao Zhou, Ruihua Liu, Xiaoyu Xu, Danbao Ma, Yun Feng, Xiang Lin","doi":"10.1093/jleuko/qiae155","DOIUrl":"https://doi.org/10.1093/jleuko/qiae155","url":null,"abstract":"<p><p>Ethnopharmacological treatments have shown beneficial effects in the clinical practice of autoimmune disorders. However, the underlying mechanism of immunomodulatory effects remains challenging, given the complicate composition of herbal medicines. Here, we developed an immunological approach to interrogate the T helper cell response. Through data mining we hypothesized that Chinese medicine formula, Yu-Ping-Feng (YPF) might be a promising candidate for treating primary Sjögren's syndrome (pSS), a common autoimmune disease manifested by exocrine gland dysfunction. We took advantage of a mouse model of experimental Sjögren's syndrome (ESS) that we previously established for YPF formula treatment. YPF therapy ameliorated the ESS pathology in mice with active disease, showing improved salivary function and decreased serum levels of autoantibodies. Phenotypic analysis suggested that both effector T and B cells were significantly suppressed. Using co-culture assay and adoptive transfer models, we demonstrated that YPF formula directly restrained effector/memory T cell expansion and differentiation into Th17 and T follicular helper (Tfh) cells, the key subsets in ESS pathogenesis. Importantly, we recruited 20 pSS patients and conducted a pilot study of 8-week therapy of YPF formula. YPF treatment effectively improved fatigue symptoms, exocrine gland functions and reduced serum IgG/IgA levels, while effector T and B cell subsets were significantly decreased. There was a trend of reduction on disease activity, but not statistically significant. Together, our findings suggested a novel approach to assess the immunomodulatory effects of YPF formula, which may be favorable for patients with autoimmune disorders.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476751","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}
Lingbiao Wang, Hao Cheng, Xiaoxia Wang, Fangming Zhu, Na Tian, Zhan Xu, Hanlin Yin, Minrui Liang, Xue Yang, Xinnan Liu, Hongying Shan, Rong Fu, Boran Cao, Dan Li, Lianbo Xiao, Liangjing Lu, Sheng-Ming Dai, Qingwen Wang, Ling Lv, Hejian Zou, Bin Li
Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.
{"title":"Deubiquitination of aryl hydrocarbon receptor (AhR) by USP21 negatively regulates Th17 cells differentiation.","authors":"Lingbiao Wang, Hao Cheng, Xiaoxia Wang, Fangming Zhu, Na Tian, Zhan Xu, Hanlin Yin, Minrui Liang, Xue Yang, Xinnan Liu, Hongying Shan, Rong Fu, Boran Cao, Dan Li, Lianbo Xiao, Liangjing Lu, Sheng-Ming Dai, Qingwen Wang, Ling Lv, Hejian Zou, Bin Li","doi":"10.1093/jleuko/qiae148","DOIUrl":"https://doi.org/10.1093/jleuko/qiae148","url":null,"abstract":"<p><p>Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476750","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}
Zhendong Wang, Erna-Zulaikha Dayang, Peter J Zwiers, Martha L Hernandez Garcia, Matthijs Luxen, Matijs van Meurs, Jan A A M Kamps, Jill Moser, Grietje Molema
Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial NF-κB p65 and MAPK c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 hours after CLP-sepsis initiation. E-selectin, not VCAM-1, was expressed in glomeruli at the same time point. In a subset of mice at 72 hours after CLP-sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 hours after CLP-sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment.
{"title":"Recruitment of neutrophils in glomeruli in early mouse sepsis is associated with E-selectin expression and activation of endothelial NF-κB and MAPK pathways.","authors":"Zhendong Wang, Erna-Zulaikha Dayang, Peter J Zwiers, Martha L Hernandez Garcia, Matthijs Luxen, Matijs van Meurs, Jan A A M Kamps, Jill Moser, Grietje Molema","doi":"10.1093/jleuko/qiae146","DOIUrl":"https://doi.org/10.1093/jleuko/qiae146","url":null,"abstract":"<p><p>Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial NF-κB p65 and MAPK c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 hours after CLP-sepsis initiation. E-selectin, not VCAM-1, was expressed in glomeruli at the same time point. In a subset of mice at 72 hours after CLP-sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 hours after CLP-sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476752","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}
Thao-Nguyen Pham, Julie Coupey, Marc Rousseau, Juliette Thariat, Samuel Valable
The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B-cells, NK-cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or Protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics were further examined using modeling. Leukocyte subpopulations interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK-cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B-cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.
淋巴细胞绝对计数(ALC)、淋巴细胞与单核细胞比值(LMR)和中性粒细胞与淋巴细胞比值(NLR)为评估癌症治疗后的全身炎症提供了便捷的方法,而炎症会影响治疗效果。了解这些生物标志物的变化和白细胞亚群的相互作用对优化放疗至关重要。在此,我们利用无肿瘤小鼠脑部照射(使用X射线或质子)期间和之后的白细胞亚群(T-CD4+、T-CD8+、B细胞、NK细胞、中性粒细胞、单核细胞)计算ALC、LMR和NLR,并通过主成分分析(PCA)评估辐射参数对其的影响。通过建模进一步研究了 NLR 动力学。白细胞亚群之间的相互作用及其对辐射参数的反应是通过 PCA 和相关分析进行检验的。在X射线照射下,ALC和LMR下降,照射后ALC恢复到基线,但LMR没有恢复到基线。在辐照期间,X射线和质子都会增加NLR,质子会恢复,但X射线不会。辐照量和剂量率对 NLR 都有明显的影响。在 X 射线和质子照射下观察到白细胞亚群相互作用,质子组在第 28 天时恢复正常。在 X 射线照射下,所有淋巴细胞亚群都出现了淋巴细胞减少症,而质子则没有。不同亚群的恢复模式各不相同。中性粒细胞计数在辐照期间增加,质子组在第 28 天前恢复,而 X 射线组则没有。在 X 射线照射下,NK 细胞和骨髓亚群之间的相互作用很明显,但质子则不明显。重要的是,髓系细胞和T/B细胞之间没有发现相互作用,这表明LMR和NLR的变化主要是由于对脑辐照的独立反应。研究人员利用无肿瘤实验小鼠模型来研究脑放射治疗对全身免疫的影响。在对全脑或半脑进行总剂量为20Gy的垂直射线分次照射时,质子照射与X射线相比对无肿瘤啮齿类动物免疫系统的不良影响较小。
{"title":"Revealing the effect of X-ray or proton brain irradiation on systemic inflammation and leukocyte subpopulation interplay in rodents.","authors":"Thao-Nguyen Pham, Julie Coupey, Marc Rousseau, Juliette Thariat, Samuel Valable","doi":"10.1093/jleuko/qiae156","DOIUrl":"https://doi.org/10.1093/jleuko/qiae156","url":null,"abstract":"<p><p>The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B-cells, NK-cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or Protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics were further examined using modeling. Leukocyte subpopulations interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK-cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B-cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476780","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}
Xin Zhuang, Peng Chen, Kaiqian Yang, Rong Yang, Xiaoying Man, Ruochen Wang, Yifen Shi
Regulated cell death (RCD) plays a crucial role in the initiation and progression of tumors, particularly in acute myeloid leukemia (AML). This study investigates the prognostic importance of RCD-related genes in AML and their correlation with immune infiltration.We combined TCGA and GTEx data, analyzing 1488 RCD-related genes, to develop a predictive model using LASSO regression and survival analysis. The model's accuracy was validated against multiple databases, examining immune cell infiltration, therapy responses, and drug sensitivity among risk groups. RT-qPCR confirmed MT1E expression in AML patients and healthy bone marrow. CCK8 and Transwell assays measured cell proliferation, adhesion, migration, and invasion, while flow cytometry and Western blotting assessed apoptosis and protein expression.We developed a prognostic model using 10 RCD methods, which demonstrated strong predictive ability, showing an inverse correlation between age and risk scores with survival in AML patients. Functional enrichment analysis of the model is linked to immune modulation pathways. RT-qPCR revealed significantly lower MT1E expression in AML versus healthy bone marrow (p<0.05). Consequently, experiments were designed to assess the function of MT1E overexpression.Findings indicated that MT1E overexpression showed it significantly reduced THP-1 cell proliferation and adhesion(p<0.001), decreased migration(p<0.001) and invasiveness(p<0.05), and increased apoptosis(p<0.05), with a notable rise in Caspase3 expression.A novel AML RCD risk model was developed, showing promise as a prognostic marker for evaluating outcomes and immune therapy effectiveness. Insights into MT1E's impact on AML cell proliferation and apoptosis open possibilities for improving patient outcomes and devising personalized treatment strategies.
{"title":"MT1E in AML: A Gateway to Understanding Regulatory Cell Death and Immunotherapeutic Responses.","authors":"Xin Zhuang, Peng Chen, Kaiqian Yang, Rong Yang, Xiaoying Man, Ruochen Wang, Yifen Shi","doi":"10.1093/jleuko/qiae151","DOIUrl":"https://doi.org/10.1093/jleuko/qiae151","url":null,"abstract":"<p><p>Regulated cell death (RCD) plays a crucial role in the initiation and progression of tumors, particularly in acute myeloid leukemia (AML). This study investigates the prognostic importance of RCD-related genes in AML and their correlation with immune infiltration.We combined TCGA and GTEx data, analyzing 1488 RCD-related genes, to develop a predictive model using LASSO regression and survival analysis. The model's accuracy was validated against multiple databases, examining immune cell infiltration, therapy responses, and drug sensitivity among risk groups. RT-qPCR confirmed MT1E expression in AML patients and healthy bone marrow. CCK8 and Transwell assays measured cell proliferation, adhesion, migration, and invasion, while flow cytometry and Western blotting assessed apoptosis and protein expression.We developed a prognostic model using 10 RCD methods, which demonstrated strong predictive ability, showing an inverse correlation between age and risk scores with survival in AML patients. Functional enrichment analysis of the model is linked to immune modulation pathways. RT-qPCR revealed significantly lower MT1E expression in AML versus healthy bone marrow (p<0.05). Consequently, experiments were designed to assess the function of MT1E overexpression.Findings indicated that MT1E overexpression showed it significantly reduced THP-1 cell proliferation and adhesion(p<0.001), decreased migration(p<0.001) and invasiveness(p<0.05), and increased apoptosis(p<0.05), with a notable rise in Caspase3 expression.A novel AML RCD risk model was developed, showing promise as a prognostic marker for evaluating outcomes and immune therapy effectiveness. Insights into MT1E's impact on AML cell proliferation and apoptosis open possibilities for improving patient outcomes and devising personalized treatment strategies.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468630","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}
Mast cells are hematopoietic-derived immune cells that possess numerous cytoplasmic granules containing immune mediators such as cytokines and histamine. Antigen stimulation triggers mast cell granule exocytosis, releasing granule contents in a process known as degranulation. We have shown that Rho GTPase signaling is an essential component of granule exocytosis, however the proteins that regulate Rho GTPases during this process are not well-defined. Here we examined the role of Rho guanine-nucleotide dissociation inhibitors (RhoGDIs) in regulating Rho GTPase signaling using RBL-2H3 cells as a mast cell model. We found that RBL-2H3 cells express two RhoGDI isoforms which are primarily localized to the cytosol. Knockdown of RhoGDI1 and RhoGDI2 greatly reduced the levels of all Rho GTPases tested: RhoA, RhoG, Rac1, Rac2 and Cdc42. The reduction in Rho GTPase levels was accompanied by an increase in their membrane-localized fraction and an elevation in the levels of active Rho GTPases. All RhoGDI knockdown strains had altered resting cell morphology, although each strain was activation competent when stimulated. Live cell imaging revealed that the RhoGDI1/2 double knockdown strain maintained its activated state for prolonged periods of time compared to the other strains. Only the RhoGDI1/2 double knockdown strain showed a significant increase in granule exocytosis. Conversely, RhoGDI overexpression in RBL-2H3 cells did not noticeably affect Rho GTPases or degranulation. Based on these results, RhoGDIs act as negative regulators of Rho GTPases during mast cell degranulation, and inhibit exocytosis by sequestering Rho GTPases in the cytosol.
{"title":"RhoGDI in RBL-2H3 cells acts as a negative regulator of Rho GTPase signaling to inhibit granule exocytosis.","authors":"Eric L Zhang, Jennifer Van Petten, Gary Eitzen","doi":"10.1093/jleuko/qiae150","DOIUrl":"https://doi.org/10.1093/jleuko/qiae150","url":null,"abstract":"<p><p>Mast cells are hematopoietic-derived immune cells that possess numerous cytoplasmic granules containing immune mediators such as cytokines and histamine. Antigen stimulation triggers mast cell granule exocytosis, releasing granule contents in a process known as degranulation. We have shown that Rho GTPase signaling is an essential component of granule exocytosis, however the proteins that regulate Rho GTPases during this process are not well-defined. Here we examined the role of Rho guanine-nucleotide dissociation inhibitors (RhoGDIs) in regulating Rho GTPase signaling using RBL-2H3 cells as a mast cell model. We found that RBL-2H3 cells express two RhoGDI isoforms which are primarily localized to the cytosol. Knockdown of RhoGDI1 and RhoGDI2 greatly reduced the levels of all Rho GTPases tested: RhoA, RhoG, Rac1, Rac2 and Cdc42. The reduction in Rho GTPase levels was accompanied by an increase in their membrane-localized fraction and an elevation in the levels of active Rho GTPases. All RhoGDI knockdown strains had altered resting cell morphology, although each strain was activation competent when stimulated. Live cell imaging revealed that the RhoGDI1/2 double knockdown strain maintained its activated state for prolonged periods of time compared to the other strains. Only the RhoGDI1/2 double knockdown strain showed a significant increase in granule exocytosis. Conversely, RhoGDI overexpression in RBL-2H3 cells did not noticeably affect Rho GTPases or degranulation. Based on these results, RhoGDIs act as negative regulators of Rho GTPases during mast cell degranulation, and inhibit exocytosis by sequestering Rho GTPases in the cytosol.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468631","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}
Chi Ma, FuKun W Hoffmann, Ashley E Shay, Imhoi Koo, Kathy A Green, William R Green, Peter R Hoffmann
The mechanisms driving metabolic reprogramming during B cell activation are unclear, particularly roles for enzymatic pathways involved in lipid remodeling. We found that murine B cell activation with lipopolysaccharide (LPS) led to a 1.6-fold increase in total lipids that included higher levels of phosphatidylethanolamine (PE) and plasmenyl PE. Selenoprotein I (SELENOI) is an ethanolamine phospholipid transferase involved in the synthesis of both PE and plasmenyl PE, and SELENOI expression was also upregulated during activation. Selenoi knockout (KO) B cells exhibited decreased levels of plasmenyl PE, which plays an important antioxidant role. Lipid peroxidation was measured and found to increase ∼2-fold in KO vs. wild-type (WT) B cells. Cell death was not impacted by KO in LPS-treated B cells and proliferation was only slightly reduced, but differentiation into CD138 + Blimp-1+ plasma B cells was decreased ∼2-fold. This led to examination of B cell receptors important for differentiation that recognize the ligand B cell activating factor, and levels of TACI (transmembrane activator, calcium-modulator, and cytophilin ligand interactor) (CD267) were significantly decreased on KO B cells compared with WT control cells. Vaccination with ovalbumin/adjuvant led to decreased ovalbumin-specific immunoglobulin M (IgM) levels in sera of KO mice compared with WT mice. Real-time polymerase chain reaction analyses revealed a decreased switch from surface to secreted IgM in spleens of KO mice induced by vaccination or LP-BM5 retrovirus infection. Overall, these findings detail the lipidomic response of B cells to LPS activation and reveal the importance of upregulated SELENOI for promoting differentiation into IgM-secreting plasma B cells.
B细胞活化过程中代谢重塑的驱动机制尚不清楚,尤其是参与脂质重塑的酶通路的作用。我们发现,用脂多糖(LPS)激活小鼠 B 细胞会导致总脂质增加 1.6 倍,其中包括更高水平的磷脂酰乙醇胺(PE)和磷脂酰 PE。硒蛋白 I(SELENOI)是一种[62] 乙醇胺磷脂转移酶,参与 PE 和磷脂酰 PE 的合成。SELENOI基因敲除(KO)的B细胞表现出塑门冬酰胺基PE水平的下降,而塑门冬酰胺基PE具有重要的抗氧化作用。对脂质过氧化进行测量后发现,KO 与 WT B 细胞相比,脂质过氧化增加了 2 倍。在 LPS 处理的 B 细胞中,细胞死亡不受 KO 的影响,增殖也只是略有减少,但分化成 CD138 + Blimp-1+ 浆 B 细胞的数量减少了 2 倍。这导致了对识别配体 B 细胞活化因子(BAFF)的 B 细胞分化重要受体的检测,与 WT 对照组相比,KO B 细胞上跨膜活化剂和钙调节剂及细胞嗜蛋白配体相互作用因子(TACI;CD267)的水平显著下降。与 WT 小鼠相比,接种卵清蛋白(OVA)/佐剂会导致 KO 小鼠血清中的 OVA 特异性 IgM 水平下降。实时 PCR 分析表明,在接种疫苗或 LP-BM5 逆转录病毒感染的诱导下,KO 小鼠脾脏中表面 IgM 向分泌型 IgM 的转换减少。总之,这些发现详细说明了 B 细胞对 LPS 激活的脂质体反应,并揭示了上调的 SELENOI 对促进分化为分泌 IgM 的浆 B 细胞的重要性。
{"title":"Upregulated selenoprotein I during lipopolysaccharide-induced B cell activation promotes lipidomic changes and is required for effective differentiation into IgM-secreting plasma B cells.","authors":"Chi Ma, FuKun W Hoffmann, Ashley E Shay, Imhoi Koo, Kathy A Green, William R Green, Peter R Hoffmann","doi":"10.1093/jleuko/qiae024","DOIUrl":"10.1093/jleuko/qiae024","url":null,"abstract":"<p><p>The mechanisms driving metabolic reprogramming during B cell activation are unclear, particularly roles for enzymatic pathways involved in lipid remodeling. We found that murine B cell activation with lipopolysaccharide (LPS) led to a 1.6-fold increase in total lipids that included higher levels of phosphatidylethanolamine (PE) and plasmenyl PE. Selenoprotein I (SELENOI) is an ethanolamine phospholipid transferase involved in the synthesis of both PE and plasmenyl PE, and SELENOI expression was also upregulated during activation. Selenoi knockout (KO) B cells exhibited decreased levels of plasmenyl PE, which plays an important antioxidant role. Lipid peroxidation was measured and found to increase ∼2-fold in KO vs. wild-type (WT) B cells. Cell death was not impacted by KO in LPS-treated B cells and proliferation was only slightly reduced, but differentiation into CD138 + Blimp-1+ plasma B cells was decreased ∼2-fold. This led to examination of B cell receptors important for differentiation that recognize the ligand B cell activating factor, and levels of TACI (transmembrane activator, calcium-modulator, and cytophilin ligand interactor) (CD267) were significantly decreased on KO B cells compared with WT control cells. Vaccination with ovalbumin/adjuvant led to decreased ovalbumin-specific immunoglobulin M (IgM) levels in sera of KO mice compared with WT mice. Real-time polymerase chain reaction analyses revealed a decreased switch from surface to secreted IgM in spleens of KO mice induced by vaccination or LP-BM5 retrovirus infection. Overall, these findings detail the lipidomic response of B cells to LPS activation and reveal the importance of upregulated SELENOI for promoting differentiation into IgM-secreting plasma B cells.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642288","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}
{"title":"Correction to: A novel opsonic eCIRP inhibitor for lethal sepsis.","authors":"","doi":"10.1093/jleuko/qiae119","DOIUrl":"10.1093/jleuko/qiae119","url":null,"abstract":"","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200193","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}
Chronic obstructive pulmonary disease (COPD) is caused by the inhalation of noxious particles such as cigarette smoke. The pathophysiological features include airway inflammation, alveolar destruction and poorly reversible airflow obstruction. A sub-group of COPD patients have higher blood eosinophil counts (BECs), associated with an increased response to inhaled corticosteroids and increased biomarkers of pulmonary type 2 (T2) inflammation. Emerging evidence shows that COPD patients with increased pulmonary eosinophil counts have an altered airway microbiome. Higher BECs are also associated with increased lung function decline, implicating T2 inflammation in progressive pathophysiology in COPD. We provide a narrative review of the role of eosinophils and T2 inflammation in the pathophysiology of COPD, encompassing the lung microbiome, pharmacological targeting of T2 pathways in COPD, and the clinical use of BEC as a COPD biomarker.
{"title":"The relevance of eosinophils in chronic obstructive pulmonary disease: inflammation, microbiome and clinical outcomes.","authors":"Andrew Higham, Augusta Beech, Dave Singh","doi":"10.1093/jleuko/qiae153","DOIUrl":"https://doi.org/10.1093/jleuko/qiae153","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is caused by the inhalation of noxious particles such as cigarette smoke. The pathophysiological features include airway inflammation, alveolar destruction and poorly reversible airflow obstruction. A sub-group of COPD patients have higher blood eosinophil counts (BECs), associated with an increased response to inhaled corticosteroids and increased biomarkers of pulmonary type 2 (T2) inflammation. Emerging evidence shows that COPD patients with increased pulmonary eosinophil counts have an altered airway microbiome. Higher BECs are also associated with increased lung function decline, implicating T2 inflammation in progressive pathophysiology in COPD. We provide a narrative review of the role of eosinophils and T2 inflammation in the pathophysiology of COPD, encompassing the lung microbiome, pharmacological targeting of T2 pathways in COPD, and the clinical use of BEC as a COPD biomarker.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468632","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}
Lymph node stromal cells (LNSCs) are an often overlooked component of the immune system but play a crucial role in maintaining tissue homeostasis and orchestrating immune responses. Our understanding of the functions these cells serve in the context of bacterial infections remains limited. We previously showed that Listeria monocytogenes, a facultative intracellular foodborne bacterial pathogen, must replicate within an as-yet-unidentified cell type in the mesenteric lymph node (MLN) to spread systemically. Here, we show that L. monocytogenes could invade, escape from the vacuole, replicate exponentially, and induce a type I interferon response in the cytosol of 2 LNSC populations infected in vitro, fibroblastic reticular cells (FRCs) and blood endothelial cells (BECs). Infected FRCs and BECs also produced a significant chemokine and proinflammatory cytokine response after in vitro infection. Flow cytometric analysis confirmed that GFP+ L. monocytogenes were associated with a small percentage of MLN stromal cells in vivo following foodborne infection of mice. Using fluorescent microscopy, we showed that these cell-associated bacteria were intracellular L. monocytogenes and that the number of infected FRCs and BECs changed over the course of a 3-day infection in mice. Ex vivo culturing of these infected LNSC populations revealed viable, replicating bacteria that grew on agar plates. These results highlight the unexplored potential of FRCs and BECs to serve as suitable growth niches for L. monocytogenes during foodborne infection and to contribute to the proinflammatory environment within the MLN that promotes clearance of listeriosis.
淋巴结基质细胞(LNSC)是免疫系统中一个经常被忽视的组成部分,但却在维持组织稳态和协调免疫反应方面发挥着至关重要的作用。我们对这些细胞在细菌感染中的功能的了解仍然有限。我们之前研究发现,单核细胞增生李斯特菌是一种变性细胞内食源性细菌病原体,它必须在肠系膜淋巴结(MLN)中一种尚未确定的细胞类型中复制才能进行系统性传播。在这里,我们展示了单核细胞增多症可以入侵、逃出液泡、指数复制,并在体外感染的两种 LNSC 群体(成纤维网状细胞(FRC)和血液内皮细胞(BEC))的细胞膜中诱导 I 型 IFN 反应。体外感染后,受感染的 FRC 和 BEC 也产生了明显的趋化因子和促炎细胞因子反应。流式细胞分析证实,小鼠经食物感染后,体内一小部分 MLN 基质细胞与 GFP+单核细胞增多症相关。利用荧光显微镜,我们发现这些与细胞相关的细菌是细胞内的单核细胞增多性淋巴瘤,在小鼠三天的感染过程中,受感染的 FRC 和 BEC 的数量发生了变化。对这些受感染的 LNSC 群体进行体内外培养发现,琼脂平板上生长的细菌具有存活和复制能力。这些结果突出表明,在食源性感染期间,FRC 和 BEC 有可能成为单核细胞增生性酵母菌的合适生长龛位,并对促进李斯特菌病清除的 MLN 内的促炎环境做出贡献。
{"title":"Lymph node stromal cells vary in susceptibility to infection but can support the intracellular growth of Listeria monocytogenes.","authors":"Jamila S Tucker, Hiba Khan, Sarah E F D'Orazio","doi":"10.1093/jleuko/qiae040","DOIUrl":"10.1093/jleuko/qiae040","url":null,"abstract":"<p><p>Lymph node stromal cells (LNSCs) are an often overlooked component of the immune system but play a crucial role in maintaining tissue homeostasis and orchestrating immune responses. Our understanding of the functions these cells serve in the context of bacterial infections remains limited. We previously showed that Listeria monocytogenes, a facultative intracellular foodborne bacterial pathogen, must replicate within an as-yet-unidentified cell type in the mesenteric lymph node (MLN) to spread systemically. Here, we show that L. monocytogenes could invade, escape from the vacuole, replicate exponentially, and induce a type I interferon response in the cytosol of 2 LNSC populations infected in vitro, fibroblastic reticular cells (FRCs) and blood endothelial cells (BECs). Infected FRCs and BECs also produced a significant chemokine and proinflammatory cytokine response after in vitro infection. Flow cytometric analysis confirmed that GFP+ L. monocytogenes were associated with a small percentage of MLN stromal cells in vivo following foodborne infection of mice. Using fluorescent microscopy, we showed that these cell-associated bacteria were intracellular L. monocytogenes and that the number of infected FRCs and BECs changed over the course of a 3-day infection in mice. Ex vivo culturing of these infected LNSC populations revealed viable, replicating bacteria that grew on agar plates. These results highlight the unexplored potential of FRCs and BECs to serve as suitable growth niches for L. monocytogenes during foodborne infection and to contribute to the proinflammatory environment within the MLN that promotes clearance of listeriosis.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983103","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}