Abstract The inflammatory response is critical in tissue healing. While extensively explored at the site of injury, relatively little is known about how injury at a remote site communicates back to the bone marrow to regulate the systemic immune response. Previous studies have demonstrated that hematopoietic stem cells (HSCs) can directly respond to secreted cytokines derived from the injury site. However, this model is limited by the need to reach a critical threshold of cytokines within the blood prior to the bone marrow HSCs responding, limiting overall responsiveness. Using our established model of polytrauma-induced heterotopic ossification (HO), we have identified the immunomodulatory metabolite itaconate as being highly and specifically enriched within the injury site. Using single cell RNA sequencing and metabolomics, combined with molecular and histological validation, we found that itaconate is made exclusively within highly mature neutrophils. Our previous work has demonstrated a direct role of myeloid-lineage cell-derived itaconate in mitigating HO formation. However, these studies identified a secondary effect of itaconate as a novel modulator of hematopoiesis. Our preliminary data show that itaconate is made exclusively in injury site neutrophils, stimulated by TLR9 activation. Itaconate production in these mature, injury site neutrophils is facilitated through changes in neutrophil metabolism, including shifts in glucose and glutamine usage through the glycolytic and oxidative phosphorylation pathways. These itaconate-laden neutrophils are able to extravasate from the injured tissue and home back to the bone marrow. Once in the bone marrow, neutrophils are phagocytosed by macrophages, inhibiting macrophage Il1b expression, a known regulator of HSC differentiation, in an itaconate-dependent manner. These preliminary findings support our central hypothesis that neutrophils serve as an itaconate-dependent systemic sensor, coupling local extremity injury to systemic inflammation by regulating BM hematopoiesis. This conceptual model will be explored in studies divided into two Specific Aims. Specific Aim 1 will identify the transcriptional and metabolic regulation of neutrophils which induces expression of Acod1 and production of itaconate specifically within the injury site. Specific Aim 2 will map the cycling of itaconate-laden neutrophils from the injury site back to the bone marrow and determine how clearance of these neutrophils by macrophages results in hematopoietic skewing. Our results should provide a new mechanism through which the body coordinates activation of the local and systemic immune response following injury.