Current Understanding in Neutrophil Differentiation and Heterogeneity

Abstract

Neutrophils are professional phagocytes that conduct effectors functions in the innate immune systems. They are differentiated in the bone marrow (BM) and terminally differentiated neutrophils are then released into systemic circulation. Neutrophils migrate into inflammatory foci through extravasation, reverse transmigration, and chemotaxis. As neutrophils arrive at a target site, they actively participate in eliminating pathogens. They phagocytose bacteria, and eliminate them through the generation of reactive oxygen species (ROS), release of protease-enriched granules, and formation of neutrophil extracellular traps (NETs). Since neutrophils are equipped with toxic arsenals, the activation of neutrophils is tightly controlled. Priming is the process of unlocking safety mechanisms before complete activation of neutrophils. Since the first discovery of neutrophils, they were considered as a homogeneous population with an inflammatory phenotype. However, heterogenous populations of neutrophils were discovered under physiological and pathological conditions. This review outlines the normal differentiation of neutrophils in the BM, and discusses the current understandings of neutrophil heterogeneity.

Keywords: Differentiation; Heterogeneity; Low-density neutrophil; Neutrophils; Normal-density neutrophil; Phenotype.

Figure 1

Trafficking of neutrophils in the BM. The granulopoietic compartments of neutrophils are divided into 3 different pools. Neutrophils express and shed various receptors according to their different developmental stages. CXCR2 is upregulated whereas CXCR4 and VLA-4 are downregulated. CXCR1 is constitutively expressed during neutrophil maturation. Retention of neutrophils is mediated by CXCR4/CXCL12 and VLA-4/VCAM-1 pathways. Immature neutrophils adhere to the marrow endothelial cells and stromal cells via the CXCR4/CXCL12 and VLA-4/VCAM-1 axes. The CXCR2/CXCL2-ligands induces neutrophil egress from the BM. Mature CXCR2^hi CXCR4^low neutrophils preferentially egress from the BM depending on CXCR2-ligands. G-CSF orchestrate s the trafficking of neutrophils in the BM. G-CSF induces the proliferation of granulocytic progenitors and enhances the egress of neutrophils by inhibiting CXCR4/CXCL12. DCs regulate G-CSF production in the BM. Aged neutrophils are cleared by the BM. Senescent neutrophils show decreased expressions of CXCR2 and CD62L with increased expressions of CXCR4 and CCR5. This surface marker profile of aged neutrophils ensures homing back to the BM where BM macrophages destroy the aged neutrophils.

Figure 2

Different phenotypes of circulating neutrophils. Based on their weight, neutrophils are divided into either NDNs and LDNs. NDNs include immature neutrophils, resting neutrophils, primed neutrophils, and activated neutrophils. LDNs include immature LDNs, pro-inflammatory LDNs, immunosuppressive LDNs, and exhausted neutrophils. Immature LDNs and proinflammatory LDNs are further classified as inflammatory LDNs, whereas immunosuppressive LDNs and exhausted neutrophils are classified as suppressive LDNs. Although this illustration depicts a schematic classification of neutrophils, it is still unclear whether these are distinct neutrophil subsets.