The neutrophil: one cell on many missions or many cells with different agendas?

Abstract

The unique role of neutrophils in host defense is not only based on their abilities to kill bacteria but is also due to their abundance in circulation and their ability to quickly migrate and accumulate in great numbers at afflicted sites. The high number of circulating neutrophils is the result of regulated release of new neutrophils from bone marrow as well as from marginated pools to balance their recruitment to tissue. Marginated pools, such as the spleen and lung, have previously been attributed to passively delay neutrophil transit time due to their large capillary network, but recent reports demonstrate that they are comprised of neutrophils with specific functions. The spleen, for instance, holds neutrophil subpopulations at different anatomical locations with distinct functions important for, e.g., bacterial eradication, and the lung was recently shown to re-educate neutrophils that had trafficked from a site of sterile injury to home back to bone marrow for elimination. Further, recent reports demonstrate subpopulations of neutrophils with different actions during homeostasis, infection, tissue restitution and cancer. It is becoming increasingly clear that this cannot be due to different stages of neutrophil activation during their life span but instead points towards distinct subpopulations of neutrophils with different effector functions. Whether these cellular distinctions are due to different education or origin is, however, not yet known. Together, the accumulating information about the heterogeneous neutrophils presents important insights into their role in development of pathologies, as well as revealing novel targets in the form of certain subpopulations to treat disease.

Keywords: Development; Lung; Marginated pools; Spleen; Subpopulations.

Fig. 1

The life of a neutrophil. Neutrophils are generated through granulopoiesis in the bone marrow. They are released into the blood circulation through decreased CXCR4-CXCL12 signaling. Upon injury/infection/hypoxia in tissue, the endothelium will signal to induce the leukocyte recruitment cascade involving rolling, adhesion, crawling, and extravasation. Neutrophils can be recruited to a range of different tissue needs such as infection, sterile injury, and hypoxia. A recently discovered feature of the neutrophil is the ability to leave an injured site to reverse transmigrate into the blood stream to further age and home to the bone marrow to be cleared, also in a CXCR4-CXCL12-dependent manner. HSC hematopoietic stem cell, CXCR CXC chemokine receptors, PSGL-1 P-selectin glycoprotein ligand-1, LFA-1 - lymphocyte function-associated antigen-1, VLA-4 very late antigen-4, Mac-1 macrophage-1 antigen, DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, VEGF-A vascular endothelial growth factor-A, VEGFR1 vascular endothelial growth factor receptor-1, MMP-9 matrix metalloproteinase-9

Figure 2

Reverse transmigration and peripheral pools. Neutrophils have recently been found to be able to exit damaged tissue (sterile inflammation or ischemic tissue), and re-enter the blood stream. They thereafter enter marginated pools such as the lung vasculature where they are re-educated to upregulate CXCR4 and later home to the bone marrow for elimination