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

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.