Metabolic flexibility and expression of CD98 define the low density neutrophils mobilised in response to G-CSF

Low density neutrophils (LDN) co-purify with mononuclear cells during density-gradient separation of peripheral blood. LDN are rarely detected in healthy individuals but appear in the peripheral blood (PB) of patients with inflammatory diseases, malignancies and in individuals treated with granulocyte colony-stimulating factor (G-CSF). Using human G-CSF mobilized LDN, this study reveals that LDN are transcriptionally, proteomically and metabolically distinct from other neutrophils. Single Cell RNAseq analysis reveals that LDN from these donors comprise one major population, with multiple interrelated transcriptional states, representing the continuum of neutrophil maturation. LDN can engage both glycolysis and mitochondrial respiration to meet energy demands, which affords increased metabolically flexibility in the nutrient perturbed tissue environments found in tumours and inflammatory diseases. This study also identifies upregulated expression of CD98, a transporter for branch chain and aromatic amino acids, as a cell surface marker for LDN in peripheral blood. CD98 may contribute to the functional properties of LDNs and represents a useful phenotypic marker.