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

Author:

Czech Marie12ORCID,Schneider Sophia1ORCID,Peltokangas Nina234ORCID,El Khawanky Nadia1256,Ghimire Sakhila7,Andrieux Geoffroy8ORCID,Hülsdünker Jan12ORCID,Krausz Máté291011ORCID,Proietti Michele91213ORCID,Braun Lukas M.12ORCID,Rückert Tamina12ORCID,Langenbach Marlene12ORCID,Schmidt Dominik12ORCID,Martin Ina12,Wenger Valentin1ORCID,de Vega Enrique12,Haring Eileen12ORCID,Pourjam Mohsen14ORCID,Pfeifer Dietmar1ORCID,Schmitt-Graeff Annette15ORCID,Grimbacher Bodo9161718ORCID,Aumann Konrad19ORCID,Kircher Brigitte20ORCID,Tilg Herbert21,Raffatellu Manuela222324ORCID,Thiele Orberg Erik72526ORCID,Häcker Georg27,Duyster Justus12829ORCID,Köhler Natalie118ORCID,Holler Ernst7ORCID,Nachbaur David20ORCID,Boerries Melanie828ORCID,Gerner Romana R.530ORCID,Grün Dominic4,Zeiser Robert12829ORCID

Affiliation:

1. Department of Medicine I, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

2. Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.

3. Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.

4. Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, 97078 Würzburg, Germany.

5. Department of Medicine III, University Hospital rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany.

6. TranslaTUM, Center for Translational Cancer Research, 81675 Munich, Germany.

7. Department of Internal Medicine III, Haematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany.

8. Institute of Medical Bioinformatics and Systems Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany.

9. Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, 79106 Freiburg, Germany.

10. Department of Rheumatology and Clinical Immunology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

11. Institute for Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

12. Department of Rheumatology and Clinical Immunology, Hannover Medical School, 30625 Hannover, Germany.

13. RESIST–Cluster of Excellence 2155, Hannover Medical School, 30625 Hannover, Germany.

14. Core Facility Microbiome, ZIEL Institute of Food and Health, Technical University of Munich, 85354 Freising, Germany.

15. University of Freiburg, 79085 Freiburg, Germany.

16. DZIF–German Center for Infection Research, Satellite Center Freiburg, 79106 Freiburg, Germany.

17. RESIST–Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Germany.

18. CIBSS–Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.

19. Department of Pathology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

20. Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria.

21. Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology and Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria.

22. Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California San Diego, La Jolla, CA 92123-0735, USA.

23. Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA.

24. Chiba University–UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, CA 92093, USA.

25. German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, 81675 Munich, Germany.

26. Bavarian Cancer Research Center (BZKF), 93053 Regensburg, Germany.

27. Institute of Medical Microbiology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany.

28. German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center, University of Freiburg, 79106 Freiburg, Germany.

29. Comprehensive Cancer Center Freiburg (CCCF), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg Germany.

30. TUM School of Life Sciences Weihenstephan, ZIEL Institute for Food & Health, 85354 Freising-Weihenstephan, Germany.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

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