Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr:54:101511.
doi: 10.1016/j.smim.2021.101511. Epub 2021 Nov 4.

Colony stimulating factors in the nervous system

Violeta Chitu  1 , Fabrizio Biundo  2 , E Richard Stanley  3
Affiliations
Review

Colony stimulating factors in the nervous system

Violeta Chitu et al. Semin Immunol. 2021 Apr.

Abstract

Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.

Keywords: CSF-1; CSF-1R; G-CSF; GM-CSF; IL-34; Microglia.

PubMed Disclaimer

Conflict of interest statement

Declarations of interests: none.

Figures

Figure 1.
Figure 1.. CSF-1, GM-CSF and G-CSF receptors and their main downstream signaling pathways.
(A) The CSF-1R is a homodimeric tyrosine kinase that binds homodimers of CSF-1 or IL-34. The extracellular domain consists of five immunoglobulin (Ig)-like domains. Ligand binding triggers downstream tyrosine phosphorylation, initiating a cascade of signaling events resulting in cell differentiation, survival, proliferation, migration and suppression of inflammation (reviewed in [2]). (B) Monomeric GM-CSF binds with relatively low affinity (nM range) to a “wrench-like” structure formed by the N-terminal Ig domain and the 2 fibronectin type III domains of the GMRα chain (GMRα). Even in the absence of the common β subunit (βc), this interaction is sufficient to elicit a biological response, i.e. glucose uptake [37]. In cells also expressing βc, the GM-CSF/GMRα complexes further associate with the β chains, creating a hexameric high-affinity receptor (100pM range) with the depicted structure. These complexes associate laterally through the GMRα subunit to form a dodecameric complex that is responsible for signaling (reviewed in [16]). Mutually exclusive phosphorylation events at βc residues, S585 or Y577, recruit either the 14–3-3 adaptor protein at low concentrations of GM-CSF (S585) or, in the setting of high GM-CSF concentrations, Shc (Y577), mediating a molecular switch between survival and survival and growth, respectively. (C) G-CSF is monomeric. The G-CSF receptor has six extracellular domains (D1-D6). D1 is an N-terminal Ig-like domain and D2-D6 are fibronectin type III domains. These are followed by a transmembrane domain and an intracellular domain without intrinsic kinase activity. D2 and D3 form the cytokine receptor homologous (CRH) module involved in ligand binding, while D4-D6 facilitate dimerization of the cytoplasmic regions. The signaling unit is a 2:2 receptor:ligand complex, in which each G-CSF monomer binds one receptor through the CRH module and the second receptor through the Ig domain (reviewed in [40]). In neurons, ligand binding activates the Erk family and enhances neuronal survival while activation of the PI3-K/Akt and STAT3 signaling pathways and prevents apoptotic cell death, by inhibiting activation of caspases and by increasing anti-apoptotic protein members such as Bcl-xL (reviewed in [42]).
Figure 2.
Figure 2.. Cellular sources of CSF-1, IL-34, GM-CSF and G-CSF and their effects on target cells in the nervous system.
The relationships between individual cytokines and their source, target and the outcome of target activation, are color coded. Dashed lines indicate that cytokine expression requires an activation signal. Grey lines and font indicate controversial, or species-specific findings. *, The effects might be indirect, as other cell types expressing the cytokine receptor were present in the culture system. **, Observed following administration in vivo.
Figure 3.
Figure 3.. Involvement of CSF-1R, GM-CSF and G-CSF in neurological disease and effects of pharmacological and genetic intervention.
(A) Animal model studies. Mixed effects, indicating that different results have been reported when the intervention was applied in different experimental settings (e.g. in acute or chronic stages of disease, in prophylactic versus therapeutic protocols, or when using different inhibitors). See the main text for details. (B) Human trials. AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CMT1X, Charcot–Marie–Tooth disease type 1X; CRL, CSF-1R-related leukoencephalopathy; GCL, globoid cell leukodystrophy; HD, Huntington’s disease; MS, multiple sclerosis; PD, Parkinson’s disease; TBI, traumatic brain injury.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Metcalf D, Hematopoietic cytokines, Blood 111(2) (2008) 485–91. - PMC - PubMed
    1. Stanley ER, Chitu V, CSF-1 receptor signaling in myeloid cells, Cold Spring Harb Perspect Biol 6(6) (2014) 1–21. - PMC - PubMed
    1. Chitu V, Caescu CI, Stanley ER, Lennartsson J, Ronnstrand L, Heldin C-H, PDGF Receptor Family, in: Wheeler DL, Yarden Y (Eds.), The Receptor Tyrosine Kinases: Family and Subfamilies, Springer Science, New York, 2015, pp. 373–538.
    1. Chitu V, Gokhan S, Nandi S, Mehler MF, Stanley ER, Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System, Trends Neurosci 39(6) (2016) 378–93. - PMC - PubMed
    1. Chitu V, Stanley ER, Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor, Curr Top Dev Biol 123 (2017) 229–275. - PMC - PubMed

Publication types

Substances