| Autor: |
Czech, Marie, Schneider, Sophia, Peltokangas, Nina, El Khawanky, Nadia, Ghimire, Sakhila, Andrieux, Geoffroy, Hülsdünker, Jan, Krausz, Máté, Proietti, Michele, Braun, Lukas M., Rückert, Tamina, Langenbach, Marlene, Schmidt, Dominik, Martin, Ina, Wenger, Valentin, de Vega, Enrique, Haring, Eileen, Pourjam, Mohsen, Pfeifer, Dietmar, Schmitt-Graeff, Annette |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/21/2024, Vol. 16 Issue 735, p1-16, 16p |
| Abstrakt: |
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. Editor's summary: An approach to treating aGVHD. Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic cell transplant (allo-HCT) for which there are limited treatment options. As aGVHD often presents with gastrointestinal (GI) tract inflammation, studying drivers of disease in the GI tract may identify new therapeutic avenues. Here, Czech et al. identified a population of lipocalin-2 (LCN2)–expressing neutrophils that were increased in the GI tract of mice with aGVHD and exhibited a tolerogenic effect by promoting IL-10 production and decreasing MHCII expression on macrophages; similar observations were made across multiple cohorts of patients who received allo-HCT. Transfer of LCN2-overexpressing neutrophils or administration of recombinant LCN2 reduced aGVHD severity across multiple murine allo-HCT models, supporting further development of LCN2 as a therapeutic for aGVHD. —Courtney Malo [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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