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

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; Grimbacher, Bodo; Aumann, Konrad; Kircher, Brigitte; Tilg, Herbert; Raffatellu, Manuela; Thiele Orberg, Erik; Häcker, Georg; Duyster, Justus; Köhler, Natalie; Holler, Ernst; Nachbaur, David; Boerries, Melanie; Gerner, Romana R; Grün, Dominic; Zeiser, Robert     «

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; Grimbacher, Bodo; Aumann, Konrad; Kircher, Brigitte; Tilg, Herbert; Raffatellu, Manuela; Thiele Orberg, Erik; Häcker, Georg; Duyster, Justus; K...     »

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.      «

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 se...     »