The Pleiotropic Effects of the GM-CSF Rheostat on Myeloid Cell Differentiation and Function: More Than a Numbers Game

Yifan Zhan, Andrew M Lew, Michael Chopin, Yifan Zhan, Andrew M Lew, Michael Chopin

Abstract

Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) is a myelopoietic growth factor that has pleiotropic effects not only in promoting the differentiation of immature precursors into polymorphonuclear neutrophils (PMNs), monocytes/macrophages (MØs) and dendritic cells (DCs), but also in controlling the function of fully mature myeloid cells. This broad spectrum of GM-CSF action may elicit paradoxical outcomes-both immunostimulation and immunosuppression-in infection, inflammation, and cancer. The complexity of GM-CSF action remains to be fully unraveled. Several aspects of GM-CSF action could contribute to its diverse biological consequences. Firstly, GM-CSF as a single cytokine affects development of most myeloid cells from progenitors to mature immune cells. Secondly, GM-CSF activates JAK2/STAT5 and also activate multiple signaling modules and transcriptional factors that direct different biological processes. Thirdly, GM-CSF can be produced by different cell types including tumor cells in response to different environmental cues; thus, GM-CSF quantity can vary greatly under different pathophysiological settings. Finally, GM-CSF signaling is also fine-tuned by other less defined feedback mechanisms. In this review, we will discuss the role of GM-CSF in orchestrating the differentiation, survival, and proliferation during the generation of multiple lineages of myeloid cells (PMNs, MØs, and DCs). We will also discuss the role of GM-CSF in regulating the function of DCs and the functional polarization of MØs. We highlight how the dose of GM-CSF and corresponding signal strength acts as a rheostat to fine-tune cell fate, and thus the way GM-CSF may best be targeted for immuno-intervention in infection, inflammation and cancer.

Keywords: GM-CSF; dendritic cells; differentiation; function; macrophages.

Copyright © 2019 Zhan, Lew and Chopin.

Figures

Figure 1
Figure 1
Schematic illustrating how GM-CSF dose selects the signal modules to be activated. Low dose GM-CSF signaling triggers Ser phosphorylation of the GM-CSFR beta chain, PI3K/Akt activation and subsequent BCL-2 enhanced survival. High dose signaling triggers Tyr phosphorylation of the GM-CSFR beta chain resulting in JAK/STAT5 activation, leading to upregulation of transcription factors PU.1 and IRF4, and downregulation of IRF8 to impact differentially on myeloid cell differentiation and function. JAK2/STAT5 activation by GM-CSF could also induce transcription of SOCS proteins to negatively regulate signaling to form a signaling regulatory loop. PI3K activation can also contribute to MØ polarization via preferential activation of Akt1 and Akt2.
Figure 2
Figure 2
Schematic illustrating how GM-CSF signaling strength affects mononuclear myeloid cell differentiation and function. Under different GM-CSF signaling strength, different types of mononuclear myeloid cells with different functional properties are differentiated. Low GM-CSF signaling strength favors development of immature DCs, intermediated signaling strength favors development of MHCIIhiCD86hi mature DCs, high signaling strength favors development of proinflammatory M1 MØs, ultra-high signaling strength favors development of suppressive M2 MØs. According to these properties, these cells could have particular impacts on immunity to autoantigens, tumors, and infection.

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