Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease,Science Translational Medicine

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Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease
Science Translational Medicine ( IF 17.1 ) Pub Date : 2024-02-21 , DOI: 10.1126/scitranslmed.adi1501
Marie Czech _{1,

2} , Sophia Schneider ₁ , Nina Peltokangas _{2,

3,

4} , Nadia El Khawanky _{1,

2,

5,

6} , Sakhila Ghimire ₇ , Geoffroy Andrieux ₈ , Jan Hülsdünker _{1,

2} , Máté Krausz _{2,

9,

10,

11} , Michele Proietti _{9,

12,

13} , Lukas M. Braun _{1,

2} , Tamina Rückert _{1,

2} , Marlene Langenbach _{1,

2} , Dominik Schmidt _{1,

2} , Ina Martin _{1,

2} , Valentin Wenger ₁ , Enrique de Vega _{1,

2} , Eileen Haring _{1,

2} , Mohsen Pourjam ₁₄ , Dietmar Pfeifer ₁ , Annette Schmitt-Graeff ₁₅ , Bodo Grimbacher _{9,

16,

17,

18} , Konrad Aumann ₁₉ , Brigitte Kircher ₂₀ , Herbert Tilg ₂₁ , Manuela Raffatellu _{22,

23,

24} , Erik Thiele Orberg _{7,

25,

26} , Georg Häcker ₂₇ , Justus Duyster _{1,

28,

29} , Natalie Köhler _{1,

18} , Ernst Holler ₇ , David Nachbaur ₂₀ , Melanie Boerries _{8,

28} , Romana R. Gerner _{5,

30} , Dominic Grün ₄ , Robert Zeiser _{1,

28,

29}

Affiliation

Department of Medicine I, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, 97078 Würzburg, Germany.
Department of Medicine III, University Hospital rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany.
TranslaTUM, Center for Translational Cancer Research, 81675 Munich, Germany.
Department of Internal Medicine III, Haematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany.
Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, 79106 Freiburg, Germany.
Department of Rheumatology and Clinical Immunology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Institute for Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Department of Rheumatology and Clinical Immunology, Hannover Medical School, 30625 Hannover, Germany.
RESIST–Cluster of Excellence 2155, Hannover Medical School, 30625 Hannover, Germany.
Core Facility Microbiome, ZIEL Institute of Food and Health, Technical University of Munich, 85354 Freising, Germany.
University of Freiburg, 79085 Freiburg, Germany.
DZIF–German Center for Infection Research, Satellite Center Freiburg, 79106 Freiburg, Germany.
RESIST–Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Germany.
CIBSS–Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
Department of Pathology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria.
Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology and Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria.
Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California San Diego, La Jolla, CA 92123-0735, USA.
Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA.
Chiba University–UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, CA 92093, USA.
German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, 81675 Munich, Germany.
Bavarian Cancer Research Center (BZKF), 93053 Regensburg, Germany.
Institute of Medical Microbiology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany.
German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center, University of Freiburg, 79106 Freiburg, Germany.
Comprehensive Cancer Center Freiburg (CCCF), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg Germany.
TUM School of Life Sciences Weihenstephan, ZIEL Institute for Food & Health, 85354 Freising-Weihenstephan, Germany.

Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.

中文翻译：

Lipocalin-2 表达可识别急性移植物抗宿主病期间肠道调节性中性粒细胞群

急性移植物抗宿主病（aGVHD）是同种异体造血细胞移植（allo-HCT）的一种危及生命的并发症，其治疗选择有限。在 aGVHD 期间促进肠道组织耐受的策略可能会改善患者的预后。通过单细胞 RNA 测序，我们在患有肠道 aGVHD 的小鼠中鉴定出了表达脂质运载蛋白 2 (LCN2) 的中性粒细胞群。转移LCN2过表达的中性粒细胞或用重组LCN2治疗可降低aGVHD的严重程度，而上皮或造血LCN2的缺乏会增强aGVHD的严重程度并导致微生物组的改变。从机制上讲，LCN2 通过 LCN2 受体 SLC22A17 诱导巨噬细胞中的胰岛素样生长因子 1 受体 (IGF-1R) 信号传导，从而增加白细胞介素 10 (IL-10) 的产生并减少主要组织相容性复合物 II 类 (MHCII) 的表达。LCN2预处理的巨噬细胞的转移降低了aGVHD的严重程度，但没有降低移植物抗白血病效应。此外，在多个 aGVHD 患者的肠道活检中，LCN2 表达与 IL-10 表达相关，并且 LCN2 诱导人巨噬细胞中的 IGF-1R 信号传导。总的来说，我们鉴定了表达 LCN2 的肠道中性粒细胞群，该群通过降低巨噬细胞中 MHCII 表达和增加 IL-10 产生来降低 aGVHD 严重程度。这项工作为 LCN2 给药作为 aGVHD 的治疗方法奠定了基础。

更新日期：2024-02-21

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