Low-Density Neutrophils: Enigmatic Cells in Health and Disease

Neutrophils have been generally considered to be homogeneous cells with only antimicrobial functions. Nowadays, however, it is clear that neutrophils are heterogeneous cells, with multiple phenotypes and functional states. One neutrophil subpopulation, the low-density neutrophils (LDN) are found among peripheral blood mononuclear cells (PBMC) after separating blood cells by density gradient centrifugation. LDN have attracted a lot of interest because they increase dramatically in several pathological conditions. LDN have been mostly studied in systemic lupus erythematosus (SLE). In this disease, LDN are prone to produce neutrophil extracellular traps (NETs) and to secrete larger amounts of proinflammatory cytokines. However, in the context of cancer, LDN are described as immunosuppressive cells and have been called granulocytic-myeloid-derived suppressor cells (G-MDSCs). Moreover, in the case of many other diseases, there is very little information on the functional properties of LDN. Hence, LDN not simply increase in numbers but become functionally different during distinct disease states. This has created confusion in the field, and the characteristics and functions of LDN continue to be a contentious issue. In this review, we aim to bring together current research in the field of LDN. We discuss discrepancies in the literature in relation to the identification and functional characterization of LDN, and also the possibility that LDN could become a biomarker for some inflammatory conditions and even novel therapeutics for certain diseases.