Mycobacterium tuberculosis Utilizes Serine/Threonine Kinase PknF to Evade NLRP3 Inflammasome-driven Caspase-1 and RIPK3/Caspase-8 Activation in Murine Dendritic Cells.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Shivangi Rastogi, Akshaya Ganesh, Volker Briken
{"title":"Mycobacterium tuberculosis Utilizes Serine/Threonine Kinase PknF to Evade NLRP3 Inflammasome-driven Caspase-1 and RIPK3/Caspase-8 Activation in Murine Dendritic Cells.","authors":"Shivangi Rastogi, Akshaya Ganesh, Volker Briken","doi":"10.4049/jimmunol.2300753","DOIUrl":null,"url":null,"abstract":"<p><p>Dendritic cells (DCs) are crucial for initiating the acquired immune response to infectious diseases such as tuberculosis. Mycobacterium tuberculosis has evolved strategies to inhibit activation of the NLRP3 inflammasome in macrophages via its serine/threonine protein kinase, protein kinase F (PknF). It is not known whether this pathway is conserved in DCs. In this study, we show that the pknF deletion mutant of M. tuberculosis (MtbΔpknF) compared with wild-type M. tuberculosis-infected cells induces increased production of IL-1β and increased pyroptosis in murine bone marrow-derived DCs (BMDCs). As shown for murine macrophages, the enhanced production of IL-1β postinfection of BMDCs with MtbΔpknF is dependent on NLRP3, ASC, and caspase-1/11. In contrast to macrophages, we show that MtbΔpknF mediates RIPK3/caspase-8-dependent IL-1β production in BMDCs. Consistently, infection with MtbΔpknF results in increased activation of caspase-1 and caspase-8 in BMDCs. When compared with M. tuberculosis-infected cells, the IL-6 production by MtbΔpknF-infected cells was unchanged, indicating that the mutant does not affect the priming phase of inflammasome activation. In contrast, the activation phase was impacted because the MtbΔpknF-induced inflammasome activation in BMDCs depended on potassium efflux, chloride efflux, reactive oxygen species generation, and calcium influx. In conclusion, PknF is important for M. tuberculosis to evade NLRP3 inflammasome-mediated activation of caspase-1 and RIPK3/caspase-8 pathways in BMDCs.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4049/jimmunol.2300753","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Dendritic cells (DCs) are crucial for initiating the acquired immune response to infectious diseases such as tuberculosis. Mycobacterium tuberculosis has evolved strategies to inhibit activation of the NLRP3 inflammasome in macrophages via its serine/threonine protein kinase, protein kinase F (PknF). It is not known whether this pathway is conserved in DCs. In this study, we show that the pknF deletion mutant of M. tuberculosis (MtbΔpknF) compared with wild-type M. tuberculosis-infected cells induces increased production of IL-1β and increased pyroptosis in murine bone marrow-derived DCs (BMDCs). As shown for murine macrophages, the enhanced production of IL-1β postinfection of BMDCs with MtbΔpknF is dependent on NLRP3, ASC, and caspase-1/11. In contrast to macrophages, we show that MtbΔpknF mediates RIPK3/caspase-8-dependent IL-1β production in BMDCs. Consistently, infection with MtbΔpknF results in increased activation of caspase-1 and caspase-8 in BMDCs. When compared with M. tuberculosis-infected cells, the IL-6 production by MtbΔpknF-infected cells was unchanged, indicating that the mutant does not affect the priming phase of inflammasome activation. In contrast, the activation phase was impacted because the MtbΔpknF-induced inflammasome activation in BMDCs depended on potassium efflux, chloride efflux, reactive oxygen species generation, and calcium influx. In conclusion, PknF is important for M. tuberculosis to evade NLRP3 inflammasome-mediated activation of caspase-1 and RIPK3/caspase-8 pathways in BMDCs.

结核分枝杆菌利用丝氨酸/苏氨酸激酶 PknF 回避小鼠树突状细胞中 NLRP3 炎症体驱动的 Caspase-1 和 RIPK3/Caspase-8 激活。
树突状细胞(DC)对于启动对结核病等传染性疾病的获得性免疫反应至关重要。结核分枝杆菌通过其丝氨酸/苏氨酸蛋白激酶--蛋白激酶 F(PknF)--进化出了抑制巨噬细胞中 NLRP3 炎症小体激活的策略。目前尚不清楚这一途径在直流电中是否保守。在这项研究中,我们发现与野生型结核杆菌感染细胞相比,结核杆菌的 pknF 缺失突变体(MtbΔpknF)能诱导小鼠骨髓源性直流细胞(BMDCs)产生更多的 IL-1β 并增加其热凋亡。与小鼠巨噬细胞的情况一样,MtbΔpknF 感染 BMDCs 后 IL-1β 生成的增加依赖于 NLRP3、ASC 和 caspase-1/11。与巨噬细胞不同,我们发现 MtbΔpknF 在 BMDCs 中介导 RIPK3/caspase-8 依赖性 IL-1β 的产生。同样,感染 MtbΔpknF 会导致 BMDCs 中的 caspase-1 和 caspase-8 激活增加。与结核杆菌感染的细胞相比,MtbΔpknF 感染的细胞产生的 IL-6 没有变化,这表明突变体不会影响炎性体激活的启动阶段。相反,激活阶段受到了影响,因为MtbΔpknF诱导的BMDCs炎症小体激活依赖于钾离子外流、氯离子外流、活性氧生成和钙离子流入。总之,PknF 对于结核杆菌逃避 NLRP3 炎症体介导的 BMDCs 中 caspase-1 和 RIPK3/caspase-8 通路的激活非常重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
×
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