Mrgpra2+ neutrophils integrate infection-derived signals to trigger NET-mediated antimicrobial defense in bone marrow.

Neutrophils are central mediators of innate defense in bone marrow, where infection rapidly reshapes local hematopoietic and immune niches. Here, we identify a subset of Mrgpra2+ neutrophils that supports antimicrobial immunity through neutrophil extracellular trap (NET) formation during bone marrow infection. Using a murine Staphylococcus aureus marrow infection model, we show that Mrgpra2 is enriched in neutrophil precursors and supports their survival and effector activation under infectious stress. Single-cell and bulk transcriptomics show that Mrgpra2+ neutrophils exhibit a transcriptional program enriched for NET formation and inflammatory signaling. Mechanistically, Mrgpra2 and TNFR signals converge on a PLC-Ca2+-PKC-NADPH oxidase axis to drive reactive oxygen species (ROS)-dependent NET release while preserving neutrophil viability. In vivo, Mrgpra2 deficiency impairs bacterial clearance, exacerbates tissue injury, and reduces the therapeutic benefit of β-defensin. These findings define a marrow neutrophil pathway that couples infection-derived signals with controlled NET deployment to preserve bone marrow immune homeostasis.