The Ontogeny of a Neutrophil: Mechanisms of Granulopoiesis and Homeostasis

Abstract

Comprising the majority of leukocytes in humans, neutrophils are the first immune cells to respond to inflammatory or infectious etiologies and are crucial participants in the proper functioning of both innate and adaptive immune responses. From their initial appearance in the liver, thymus, and spleen at around the eighth week of human gestation to their generation in large numbers in the bone marrow at the end of term gestation, the differentiation of the pluripotent hematopoietic stem cell into a mature, segmented neutrophil is a highly controlled process where the transcriptional regulators C/EBP-α and C/EBP-ε play a vital role. Recent advances in neutrophil biology have clarified the life cycle of these cells and revealed striking differences between neonatal and adult neutrophils based on fetal maturation and environmental factors. Here we detail neutrophil ontogeny, granulopoiesis, and neutrophil homeostasis and highlight important differences between neonatal and adult neutrophil populations.

Neutrophil Diversity in Health and Disease

“…Marginal zone (MZ): the region at the interface between the red and white pulp, for example of the spleen. from committed myeloid precursors that, through subsequent differentiation stages (here defined as 'immature neutrophils'), differentiate into segmented mature neutrophils [31]. Under resting conditions, only terminally differentiated neutrophils are released into the circulation and recovered as normal-density neutrophils (NDNs) (Box 1) [54].…”

“…Neutrophil ontogeny is currently recognized as a major contributor to heterogeneity [3,8,9]. Because of its rapid homeostatic turnover, the size of the circulating mature neutrophil pool is maintained by a fine balance between granulopoiesis, neutrophil release from the bone marrow (BM) into the circulation, and ultimately return to the BM for final clearance by resident macrophages [31] (Figure 1). Although the latter process has been better characterized in mice (see below), there is also evidence for neutrophil recycling and destruction within the human BM [32].…”

“…Humans Mobilization of immature CD66b + CD10 − neutrophils into the circulation (known as the 'left shift') is a well-characterized phenomenon that takes place as a consequence of emergency granulopoiesis [31], either artificially induced [e.g., by lipopolysaccharide (LPS) or G-CSF administration] or disease-associated (e.g., sepsis, infection, cancer). The renewed interest in immature CD66b + CD10 − neutrophils comes from recent evidence showing that these cells, despite their 'immature state', can perform innate immune functions (e.g., chemotaxis and antimicrobial defense) [54,60,61], as well as displaying functional plasticity and immunoregulatory properties (e.g., modulation of proliferation and cytokine production by CD4 + and CD8 + T cells) [62][63][64][65].…”

Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis

“…Neutrophils develop in the bone marrow from hematopoietic stem cells in a process called “granulopoiesis” . Granulopoiesis refers to the formation of granules within the developing neutrophil in the bone marrow between myeloblast and promyelocyte stages of development .…”

“…As the neutrophil matures, the level of CXCR4 expression decreases, while the chemokine CXCL2 and its receptor, CXCR2, increase (Figure ) . This renders them responsive to the chemokine CXCL2 and less responsive to CXCL12 and allows egress from the bone marrow into the circulation . Conventional dendritic cells (cDCs) play a role in maintaining neutrophil homeostasis and regulating neutrophil distribution between the bone marrow, peripheral blood and organs via controlled secretion of the chemokines, CXCL1, CXCL2, and CXCL10 and the growth factor, granulocyte colony‐stimulating factor (G‐CSF), although the exact mechanism remains unexplored …”