间充质基质细胞通过重新编程造血干细胞促进中性粒细胞训练的免疫。

IF 4.7 3区 医学 Q2 IMMUNOLOGY Journal of Innate Immunity Pub Date : 2023-01-01 Epub Date: 2023-10-05 DOI:10.1159/000533732
Julie Ng, Anna E Marneth, Alec Griffith, Daniel Younger, Sailaja Ghanta, Alan Jiao, Gareth Willis, Junwen Han, Jewel Imani, Bailin Niu, Joshua W Keegan, Brandon Hancock, Fei Guo, Yang Shi, Mark A Perrella, James A Lederer
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引用次数: 0

摘要

迫切需要新的治疗方法来预防正在接受癌症治疗或其他免疫抑制治疗的免疫功能低下个体的机会性感染。训练免疫力是减少这种疾病负担的一种很有前途的策略。我们之前证明,在中性粒细胞减少性败血症的小鼠模型中,用a类CpG寡核苷酸(CpG-ODN)(Toll样受体9(TLR9)激动剂)预处理的间充质基质细胞(MSC)可以增强紧急粒细胞生成。在这里,我们使用嵌合小鼠模型来证明MSC分泌旁分泌因子,这些因子作用于谱系阴性的c-kit+造血干细胞(HSC),使它们在移植数月后“准备好”增强紧急粒细胞生成。从暴露于MSCs和CpG-ODN预处理MSCs的条件培养基的HSC发育而来的嵌合小鼠在肺部感染后显示出显著更高的细菌清除率和增加的中性粒细胞粒细胞生成。通过CUT&RUN染色质测序和飞行时间细胞仪(CyTOF)方法,我们确定MSC条件培养基在HSC中通过mTOR途径在参与骨髓生成和信号持久性的基因处留下H3K4me3组蛋白标记。MSCs的可溶性因子和细胞外小泡(EV)都介导了这些对HSC的影响,质谱蛋白质组学分析显示可溶性钙网蛋白是一种潜在的介质。总之,本研究表明,经过训练的免疫可以由骨髓间充质干细胞的旁分泌因子介导,通过重新编程HSC来诱导中性粒细胞训练的免疫,以实现中性粒细胞介导的抗微生物免疫的长期功能变化。
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Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells.

Novel therapeutics are urgently needed to prevent opportunistic infections in immunocompromised individuals undergoing cancer treatments or other immune-suppressive therapies. Trained immunity is a promising strategy to reduce this burden of disease. We previously demonstrated that mesenchymal stromal cells (MSCs) preconditioned with a class A CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) agonist, can augment emergency granulopoiesis in a murine model of neutropenic sepsis. Here, we used a chimeric mouse model to demonstrate that MSCs secrete paracrine factors that act on lineage-negative c-kit+ hematopoietic stem cells (HSCs), leaving them "poised" to enhance emergency granulopoiesis months after transplantation. Chimeric mice developed from HSCs exposed to conditioned media from MSCs and CpG-ODN-preconditioned MSCs showed significantly higher bacterial clearance and increased neutrophil granulopoiesis following lung infection than control mice. By Cleavage Under Targets and Release Using Nuclease (CUT&RUN) chromatin sequencing, we identified that MSC-conditioned media leaves H3K4me3 histone marks in HSCs at genes involved in myelopoiesis and in signaling persistence by the mTOR pathway. Both soluble factors and extracellular vesicles from MSCs mediated these effects on HSCs and proteomic analysis by mass spectrometry revealed soluble calreticulin as a potential mediator. In summary, this study demonstrates that trained immunity can be mediated by paracrine factors from MSCs to induce neutrophil-trained immunity by reprogramming HSCs for long-lasting functional changes in neutrophil-mediated antimicrobial immunity.

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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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