布鲁顿酪氨酸激酶抑制可减轻炎症反应,并对小鼠和人类髓系细胞的吞噬能力和细胞代谢产生不同影响。

Q3 Medicine
Rochelle Y Benoit, Jennifer L Zagrodnik, Samantha J Carew, Craig S Moore
{"title":"布鲁顿酪氨酸激酶抑制可减轻炎症反应,并对小鼠和人类髓系细胞的吞噬能力和细胞代谢产生不同影响。","authors":"Rochelle Y Benoit, Jennifer L Zagrodnik, Samantha J Carew, Craig S Moore","doi":"10.4049/immunohorizons.2400045","DOIUrl":null,"url":null,"abstract":"<p><p>Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"8 9","pages":"652-667"},"PeriodicalIF":0.0000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447691/pdf/","citationCount":"0","resultStr":"{\"title\":\"Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells.\",\"authors\":\"Rochelle Y Benoit, Jennifer L Zagrodnik, Samantha J Carew, Craig S Moore\",\"doi\":\"10.4049/immunohorizons.2400045\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.</p>\",\"PeriodicalId\":94037,\"journal\":{\"name\":\"ImmunoHorizons\",\"volume\":\"8 9\",\"pages\":\"652-667\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447691/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ImmunoHorizons\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.4049/immunohorizons.2400045\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ImmunoHorizons","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.4049/immunohorizons.2400045","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

摘要

布鲁顿酪氨酸激酶(BTK)是一种由多种免疫细胞表达的激酶,通常在促炎状态下被激活。虽然大多数与 BTK 相关的研究历来都集中在 B 细胞上,但鉴于髓系细胞也以相当的水平表达 BTK,因此了解 BTK 在非 B 细胞群中的作用至关重要。在本研究中,我们研究并比较了抑制人类和鼠类髓系细胞中的 BTK 如何改变细胞表型和功能。所有实验均使用两种 BTK 抑制剂(evobrutinib 和 tolebrutinib)进行,这两种抑制剂目前正处于治疗多发性硬化症的后期临床试验阶段。实验评估了 BTK 抑制对细胞因子和 microRNA 表达、吞噬能力和细胞代谢的影响。在所有细胞中,evobrutinib和托乐布替尼都能显著减少磷酸化BTK和LPS诱导的细胞因子释放。抑制BTK还能明显降低髓系细胞的耗氧率和细胞外酸化率,并能明显降低鼠源细胞的吞噬能力,但不能降低人巨噬细胞的吞噬能力。为了进一步阐明其机制,我们还研究了已知会影响髓系细胞功能的 microRNA 的表达。BTK 抑制导致了 microRNA 表达谱的改变(即 miR-155-5p 减少,miR-223-3p 增加),这与促炎性骨髓细胞表型的减少是一致的。总之,这些结果进一步揭示了 BTK 抑制剂在免疫相关疾病中的作用机制,同时也强调了物种特异性和细胞特异性的重要差异,在解释和比较临床前研究与人体研究的结果时应考虑这些差异。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells.

Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
3.70
自引率
0.00%
发文量
0
审稿时长
4 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信