Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?

Abstract

Neutrophils are the most abundant leukocytes in the circulation, and have been regarded as first line of defense in the innate arm of the immune system. They capture and destroy invading microorganisms, through phagocytosis and intracellular degradation, release of granules, and formation of neutrophil extracellular traps after detecting pathogens. Neutrophils also participate as mediators of inflammation. The classical view for these leukocytes is that neutrophils constitute a homogenous population of terminally differentiated cells with a unique function. However, evidence accumulated in recent years, has revealed that neutrophils present a large phenotypic heterogeneity and functional versatility, which place neutrophils as important modulators of both inflammation and immune responses. Indeed, the roles played by neutrophils in homeostatic conditions as well as in pathological inflammation and immune processes are the focus of a renovated interest in neutrophil biology. In this review, I present the concept of neutrophil phenotypic and functional heterogeneity and describe several neutrophil subpopulations reported to date. I also discuss the role these subpopulations seem to play in homeostasis and disease.

Keywords: bacteria; cancer; infection; inflammation; neutrophil.

Figure 1

Antimicrobial mechanisms of neutrophils. When neutrophils recognize microbial pathogens, they deploy different functions to destroy them. Phagocytosis involves the ingestion of the microorganism into a phagocytic vacuole that upon maturation becomes a phagolysosome. In this new organelle, the microorganism is destroyed by the action of low pH, and degrading enzymes. Neutrophils also degranulate and release to their environment the contents of their granules. When the microorganism is too large to be ingested, neutrophil can also produce extracellular traps (NETs) formed by DNA fibers and proteins from the granules.

Figure 2

Granulopoiesis. Neutrophils are produced in the bone marrow. From a self-renewing hematopoietic stem cell (HSC), a multipotent progenitor (MPP) cell is formed. MPPs give rise to lymphoid-primed multipotent progenitors (LPMP), which differentiate into granulocyte-monocyte progenitors (GMP). These GMPs, under control of the granulocyte colony-stimulating factor (G-CSF) commit to neutrophil generation by turning into myeloblasts, which then follow a maturation process that includes the stages of promyelocyte, myelocyte, metamyelocyte, band cell, and finally a mature neutrophil.

Figure 3

Phenotype of aged neutrophils. Upon release from the bone marrow, a “fresh” neutrophil (PMN) express the surface molecules CD62L and CXCR4. After several (4–6 h) hours in the circulation neutrophils change the expression of many surface molecules. The new phenotype is described as “aged” neutrophils. These aged neutrophils are then cleared from the blood by migration into tissues or by returning to the bone marrow.

Figure 4

Neutrophil subsets that can be separated through density gradient centrifugation. The bulk of mature (normal) neutrophils (PMN) are denser and separate at the bottom of the density gradient. These cells, named high-density neutrophils present the classical neutrophil morphology with a lobulated nucleus and many granules. In the upper part of the gradient, the less dense peripheral blood mononuclear cells (PBMC) are separated. Among these cells, low-density neutrophils can be found. They comprise immature and mature neutrophils with immunosuppressive properties. The immature population is also called granulocytic myeloid derived suppressor cells (G-MDSC).

Figure 5

Neutrophils in the circulation display different phenotypes. Mature (normal) neutrophils (PMN) leave the bone marrow and display the classical pro-inflammatory and anti-tumor properties of these cells. It is thought that these PMN can migrate into tumors and display an anti-tumor (N1) phenotype. In tumor-bearing mice, immature neutrophils, such as band cells, also leave the bone marrow into the circulation. These “low-density” neutrophils include granulocytic myeloid derived suppressor cells (G-MDSC) and neutrophils with immunosuppressive properties. These cells can infiltrate tumors and display pro-tumor (N2) phenotype. Under the influence of transforming growth factor-beta (TGF-β, normal PMN can change into “low-density” neutrophils. The exact origin of recruited neutrophils is not known. Also, it is not clear if N1 cells can change into N2 cells and vice versa under the influence of the tumor microenvironment.