In vivo G-CSF Treatment Activates GR-SOCS1 Axis Suppressing IFN-? Secretion by Natural Killer Cells [Hi-C]

Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in controlling tumors or microbial infections through the production of interferon gamma (IFN-?). Granulocyte-colony stimulating factor (G-CSF) inhibits IFN-? secretion by NK cells, but the mechanism underlying this effect remains unclear. Here, by comparing the multi-omics profiles of human NK cells before and after in vivo G-CSF treatment, we identified a pathway that was activated in response to G-CSF treatment, which suppressed IFN-? secretion in NK cells. Specifically, our integrative genomic strategy revealed glucocorticoid receptor (GR) activation in NK cells that mediated the genomic response to G-CSF treatment. Activated GRs can inhibit secretion of IFN-? by promoting interactions between suppressor of cytokine signaling 1 (SOCS1) promoter and enhancer, as well as increase the expression of SOCS1. Experiments in mice confirmed that G-CSF in vivo treatment significantly down-regulated IFN-? secretion and up-regulated GR and SOCS1 expression in NK cells. In addition, GR blockade (RU486) significantly reversed the effects of G-CSF, demonstrating that GR up-regulates SOCS1 and inhibits the production of IFN-? by NK cells. Overall design: This study was designed to explore the mechanism of the suppression effect of G-CSF on IFN-? production. To this end, we generated multi-omics profile of HSC donor derived bone marrow NK cells before and after G-CSF treatment and further validated our findings in mice.