Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis

Abstract

Neutrophils are phagocytes whose principal function is to maintain anti-bacterial immunity. Neutrophils ingest and kill invading bacteria, releasing cytotoxic, chemotactic and inflammatory mediators at sites of infection. This serves to control the immediate host immune response and attract other cells, such as macrophages and dendritic cells, which are important for establishing long-term adaptive immunity. Neutrophils thus contribute to both the initiation and the maintenance of inflammation at sites of infection. Aberrant neutrophil activity is deleterious; suppressed responses can cause extreme susceptibility to infection while overactivation can lead to excessive inflammation and tissue damage. This review will focus on neutrophil regulation by granulocyte colony-stimulating factor (G-CSF), the principal cytokine controlling neutrophil development and function. The review will emphasize the molecular aspects of G-CSF-driven granulopoiesis in steady state (healthy) conditions and during demand-driven or 'emergency' conditions elicited by infection or clinical administration of G-CSF. Understanding the molecular control of granulopoiesis will aid in the development of new approaches designed to treat disorders of neutrophil production and function.

Figure 1

Schematic diagram of pathways regulating G-CSF and neutrophil production. (Right) Inflammatory stimuli in the extracellular microenvironment, such as LPS, TNFα and IL-1β act on target cells (not to scale) to induce G-CSF expression via intracellular signaling molecules such as NF-κB and C/EBPβ. (Left) IL-17 production by Th17 cells activates IL-17R signal transduction, which promotes G-CSF expression. G-CSF can be regulated by transcriptional and post-transcriptional mechanisms. (Center) The increase in G-CSF synthesis stimulates neutrophil production in the bone marrow (anatomical details are not shown). Circulating neutrophils negatively regulate the production of IL-23 and Th17 cells, providing a feedback system to control G-CSF synthesis.

Figure 2

Functions of G-CSFR tyrosine residues and receptor-activated signaling pathways. The intracellular region of the G-CSFR is illustrated (narrow green box, left; not drawn to scale), with the four tyrosine residues highlighted in black. On the left of each tyrosine residue are functions that have been assigned by in vitro and in vivo studies, including proliferation, differentiation and macrophage/granulocyte lineage-specification. On the right of each tyrosine, representations of signaling proteins that couple to specific residues are shown. The function of these molecules is listed on the right side of the figure. At the lower portion of the figure, a schematic diagram of the nucleus of a granulocytic progenitor is shown, along with additional signaling molecules that are required for ‘emergency’ granulopoiesis. References for tyrosine and signal protein function can be found in the text.

Figure 3

A timeline of major events in the development and use of G-CSF in the clinic. Left to right, the timeline highlights principal findings that are relevant to the therapeutic use of G-CSF including the initial description of congenital neutropenia [163] and leukemia in SCN [184], purification and cloning of human G-CSF [12, 15, 16], first clinical use of G-CSF for neutropenia resulting from chemotherapy or congenital origin [, , –154], cloning of G-CSFR and identification of receptor functional domains [, , –82], initial reports of G-CSFR mutations in SCN [–157], functional studies of G-CSFR mutants found in SCN [95, 96, 110, 161], and associations between the therapeutic use of G-CSF and the development of MDS/AML [9, 170, 185]. Due to space limitations, all significant references could not be included. (Timeline: Purple, 1956-1959; Pink, 1960-1969; Yellow, 1970-1979; Green, 1980-1989; Blue, 1990-1999; Red, 2000-present)