AbstractMonocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice.

摘要单核细胞通过募集到斑块中直接促进动脉粥样硬化的发展，在斑块中它们分化为巨噬细胞。在本研究中，我们询问调节单核细胞葡萄糖代谢如何影响其体内平衡及其对动脉粥样硬化的影响。在这里，我们研究循环代谢物如何控制小鼠血液，骨髓和外周组织中的单核细胞行为。

We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression.

我们发现血清葡萄糖浓度与单核细胞数量相关。在饮食限制的小鼠中，单核细胞不能从糖酵解代谢重新编程为脂肪酸氧化，导致血液中单核细胞数量减少。从机制上讲，依赖Glut1的葡萄糖代谢有助于维持单核细胞及其祖细胞上的CD115膜表达，并通过调节CCR2表达来调节单核细胞的迁移能力。

Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity.

遗传模型和药理抑制剂的结果进一步描述了不同代谢途径对CD115和CCR2表达调控的相对贡献。同时，尽管血液单核细胞数量显着减少，但Glut1抑制不会影响小鼠模型中动脉粥样硬化斑块的发展，这可能是由于剩余的单核细胞具有增加的迁移能力。

Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions..

总之，这些数据强调了葡萄糖摄取和细胞内葡萄糖代谢在控制单核细胞稳态和功能中的作用。。

IntroductionMonocytes are innate immune cells generated in the bone marrow compartment1,2. Monocytes differentiate from hematopoietic stem cells (HSCs) in a multistep tightly regulated process. In murine blood, two major monocyte populations have been distinguished according to their expression of the marker of unknown function Ly6C3.

引言单核细胞是在骨髓区室中产生的先天免疫细胞1,2。单核细胞在多步骤严格调控的过程中与造血干细胞（HSC）分化。在小鼠血液中，根据其未知功能Ly6C3标记的表达，已经区分了两个主要的单核细胞群。

Inflammatory Ly6Chigh monocytes, also called classical monocytes, highly express the chemokine receptor CCR2 and can infiltrate peripheral tissues to maintain macrophage pool homeostasis4,5,6. Patrolling Ly6Clow monocytes, also known as non-classical monocytes, sample and heal blood vessels7,8. Counterparts of murine classical and non-classical monocytes are also found in humans and are identified as CD14+ CD16- and CD14- CD16+, respectively.

炎性Ly6Chigh单核细胞，也称为经典单核细胞，高度表达趋化因子受体CCR2，可浸润外周组织以维持巨噬细胞库稳态4,5,6。巡逻Ly6Clow单核细胞，也称为非经典单核细胞，取样并愈合血管7,8。在人类中也发现了小鼠经典和非经典单核细胞的对应物，分别被鉴定为CD14+CD16-和CD14-CD16+。

Both monocyte subsets express CD115 (CSF1R) which binds M-CSF (CSF1) and IL-34, the main cytokines responsible for maintenance of tissue macrophages. The mechanisms controlling CD115 and CCR2 expression on monocytes are yet to be fully understood.Monocytes play central roles during acute and chronic inflammation2.

两种单核细胞亚群均表达CD115（CSF1R），其结合M-CSF（CSF1）和IL-34，IL-34是负责维持组织巨噬细胞的主要细胞因子。控制单核细胞上CD115和CCR2表达的机制尚未完全了解。单核细胞在急性和慢性炎症中起着核心作用2。

Their recruitment to the site of inflammation and subsequent differentiation into different subsets of tissue macrophages prevent or amplify inflammation depending on the local microenvironment. High blood monocyte counts positively associate with atherosclerosis progression in humans9,10. Thus, controlling monocyte numbers and fate decisions is of critical importance during infections and cardio-metabolic diseases.

它们募集到炎症部位并随后分化成不同的组织巨噬细胞亚群，根据局部微环境防止或放大炎症。高血单核细胞计数与人类动脉粥样硬化进展呈正相关9,10。因此，在感染和心脏代谢疾病期间，控制单核细胞数量和命运决定至关重要。

In pre-clinical models, monocytes contribute to atherosclerotic plaque growth after being recruited via chemokine receptors such as CCR2, CCR5 and CX3CR111 and differentiating into macrophages. Mice lacking CSF1 barely form plaques, suggesting a crucial role of the CSF1-CSF1R axi.

在临床前模型中，单核细胞通过趋化因子受体如CCR2，CCR5和CX3CR111募集并分化成巨噬细胞后，有助于动脉粥样硬化斑块的生长。缺乏CSF1的小鼠几乎不形成斑块，表明CSF1-CSF1R axi的关键作用。

Data availability

数据可用性

No new transcriptomic, proteomic or metabolomic datasets were generated during the study. All data supporting the findings of the study are presented in the main manuscript or in the supplementary information files. Requests relative to the flow cytometry and imaging data presented herein should be directed to corresponding authors (Stoyan.Ivanov@univ-cotedazur.fr or Alexandre.Gallerand@univ-cotedazur.fr) due to still-ongoing analysis for further exploitation of the data.

在研究期间没有产生新的转录组学，蛋白质组学或代谢组学数据集。支持研究结果的所有数据均在主要手稿或补充信息文件中提供。(Stoyan.Ivanov@univ-cotedazur.fr或Alexandre.Gallerand@univ-cotedazur.fr)由于仍在进行分析以进一步利用数据。

Access to our data shall be granted permanently to researchers who provide written research aims and are affiliated with a recognized institution. We aim to answer and provide access to requested data within 30 days. Source data are provided with this paper..

提供书面研究目标并隶属于公认机构的研究人员应永久获得我们数据的访问权。我们的目标是在30天内回答并提供对所需数据的访问。本文提供了源数据。。

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Download referencesAcknowledgementsWe would like to thank the C3M Animal facility for technical support and the GIS-IBISA multi-sites platform Microscopie Imagerie Côte d’Azur (MICA), and particularly the imaging site of C3M (INSERM U1065) supported by Conseil Régional, Conseil Départemental, and IBISA.

下载参考文献致谢我们要感谢C3M动物设施的技术支持和GIS-IBISA多站点平台Microscope Imagerie Côte d'Azur（MICA），特别是由Conseil Régional，Conseil département和IBISA支持的C3M成像站点（INSERM U1065）。

We would also like to thank the C3M flow Cytometry Core Facility financed by Conseil Général CG06 and Conseil Régional PACA. We would like to thank Dr. David Hume for kindly sharing Csf1rΔFIRE mice, and Dr. Marc Bajénoff for providing access to them. S.I. is funded by Institut National de la Sante et de la Recherche Medicale (INSERM), Agence Nationale de la Recherche (ANR-17-CE14-0017-01 and ANR-19-ECVD-0005-01) and Fondation de France.

我们还要感谢由Conseil Général CG06和Conseil Régional PACA资助的C3M流式细胞仪核心设施。我们要感谢David Hume博士与我们分享Csf1rΔFIRE小鼠，感谢Marc Bajénoff博士提供了对它们的访问。S、 。

A.G. was supported by the French government through the UCAJedi Investments in the Future projects managed by the National Research Agency (ANR) (ANR-15-IDEX-01). A.H. and C.C. are supported by ERA-CVD and FWF Austrian Science Funds (I 4646). D.D. is supported by a grant from Fondation pour la Recherche Médicale, France (EQU202303016719).Author informationAuthors and AffiliationsUniversité Côte d’Azur, CNRS, LP2M, Nice, FranceAlexandre Gallerand, Bastien Dolfi, Zakariya Caillot, Alexia Castiglione, Axelle Strazzulla, Fairouz N.

A、 G.通过UCAJedi对国家研究机构（ANR）（ANR-15-IDEX-01）管理的未来项目的投资得到了法国政府的支持。A、 H.和C.C.得到了ERA-CVD和FWF奥地利科学基金（I 4646）的支持。D、 D.得到了法国医学研究基金会（EQU202303016719）的资助。作者信息作者和附属机构蓝色大学，CNRS，LP2M，Nice，FranceAlexandre Gallerand，Bastien Dolfi，Zakariya Caillot，Alexia Castiglione，Axelle Strazzulla，Fairouz N。

Zair, Adeline Bertola, Denis Doyen, Rodolphe R. Guinamard & Stoyan IvanovUniversité Côte d’Azur, INSERM, C3M, Nice, FranceAlexandre Gallerand, Bastien Dolfi, Marion I. Stunault, Alexia Castiglione, Flora Batoul, Nathalie Vaillant, Adélie Dumont, Johanna Merlin, Jerome Gilleron, Laurent Yvan-Charvet, Rodolphe R.

扎尔（Zair）、阿德琳·贝托拉（AdelineBertola）、丹尼斯·道恩（DenisDoyen）、鲁道夫·R·吉尼亚马（RodolpheR.Guinamard）和斯托扬·伊万诺夫大学（StoyanIvanovUniversitéCôd'Azur）、INSERM、C3M、尼斯（Nice）、弗朗西娅·亚历山大·加莱兰德（FranceAlexandreGallerand）、巴斯蒂安·多尔菲（BastienDolfi）、马里恩·斯特劳特（MarionI.Stunault）、亚历克西亚·卡斯蒂格利翁（AlexiaCastiglione）、弗洛拉·巴图。

Guinamard & Stoyan IvanovDepartment of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, AustriaChuqiao Chen & Arvand HaschemiDepartment of Radiology, Washington University Sch.

Guinamard＆Stoyan IvanovDepartment of Laboratory Medicine，维也纳医科大学，1090，Australiachuqiao Chen＆Arvand HaschemiDepartment of Radiology，Washington University Sch。

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PubMed Google ScholarContributionsA.G. and S.I. designed the study. A.G. and S.I. wrote the manuscript and prepared the figures. A.G., B.D., M.I.S., Z.C., A.S., C.C., G.S.H., H.L., F.B., A.C., N.V., A.D., T.P., J.M., F.N.Z., J.G., A.B., R.R.G., and S.I. performed experiments.

PubMed谷歌学术贡献。G、 和S.I.设计了这项研究。A、 G.和S.I.撰写了手稿并准备了数字。A、 G.，B.D.，M.I.S.，Z.C.，A.S.，C.C.，G.S.H.，H.L.，F.B.，A.C.，N.V.，A.D.，T.P.，J.M.，F.N.Z.，J.G.，A.B.，R.R.G。和S.I.进行了实验。

P.C. and R.J.A. provided tools and expertise. A.G., B.D., A.B., J.W.W., D.M., D.D., L.Y.C., A.H., D.D., Y.L., R.R.G., and S.I. analyzed data and edited the manuscript. S.I. obtained funding for the project.Corresponding authorsCorrespondence to.

P、 C.和R.J.A.提供了工具和专业知识。A、 。S、 I.获得项目资金。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleGallerand, A., Dolfi, B., Stunault, M.I. et al. Glucose metabolism controls monocyte homeostasis and migration but has no impact on atherosclerosis development in mice.

转载和许可本文引用本文Gallerand，A.，Dolfi，B.，Stunault，M.I。等人。葡萄糖代谢控制单核细胞稳态和迁移，但对小鼠动脉粥样硬化的发展没有影响。

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