GM-CSF Quantity Has a Selective Effect on Granulocytic vs. Monocytic Myeloid Development and Function

Abstract

GM-CSF promotes myeloid differentiation of cultured bone marrow cells into cells of the granulocytic and monocytic lineage; the latter can further differentiate into monocytes/macrophages and dendritic cells. How GM-CSF selects for these different myeloid fates is unresolved. GM-CSF levels can change either iatrogenically (e.g., augmenting leukopoiesis after radiotherapy) or naturally (e.g., during infection or inflammation) resulting in different immunological outcomes. Therefore, we asked whether the dose of GM-CSF may regulate the development of three types of myeloid cells. Here, we showed that GM-CSF acted as a molecular rheostat where the quantity determined which cell type was favored; moreover, the cellular process by which this was achieved was different for each cell type. Thus, low quantities of GM-CSF promoted the granulocytic lineage, mainly through survival. High quantities promoted the monocytic lineage, mainly through proliferation, whereas moderate quantities promoted moDCs, mainly through differentiation. Finally, we demonstrated that monocytes/macrophages generated with different doses of GM-CSF differed in function. We contend that this selective effect of GM-CSF dose on myeloid differentiation and function should be taken into consideration during pathophysiological states that may alter GM-CSF levels and during GM-CSF agonistic or antagonistic therapy.

Human Dendritic Cells Express the Complement Receptor Immunoglobulin Which Regulates T Cell Responses

“…Both M-CSF and GM-CSF have been reported to alter DC differentiation and/or function (22,28). Examination of the effects of M-CSF and GM-CSF on the expression of CRIg in DC showed that cells treated with M-CSF display a marked increase in CRIg mRNA expression ( Figure 7A).…”

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

“…However, when GM-CSF signaling strength that is represented by both GM-CSF quantity and receptor density is high over time, monopoiesis is favored over granulopoiesis (93). In line with this predictive model, our recent data showed that high dose GM-CSF favored monopoiesis over granulopoiesis in vitro (5). Similarly, GM-CSF transgenic mice had preferential expansion of MØs in multiple organs (5, 11, 12).…”

GM-CSF-Dependent Inflammatory Pathways

“…Consistent with these dose-dependent signaling responses, dose dependent effects of a neutralizing anti-GM-CSF mAb on monocyte-derived activation/polarization vs. cell number levels were found in an inflammation model—indications were that higher local GM-CSF concentrations were needed for the activation/polarization response (30). Monocytes/macrophages generated in vivo from mouse bone marrow precursors with different concentrations of GM-CSF differed in function with possible implications for GM-CSF-dependent pathology (31)—cells generated with a high concentration of GM-CSF were more potent in generating cytokines and chemokines. The links between the various signaling pathways listed and their dependence on GM-CSF concentration in monocytes/macrophages requires further analysis to assess their contribution to the various cellular responses mentioned above.…”

“…As an advance on the use and interpretation of the data from such cultures, cell sorting strategies have isolated populations from them with macrophage and DC properties (73). Again the GM-CSF concentrations employed likely contribute to the phenotypes of the resulting populations (31). The in vivo relationships of the in vivo generated populations from mouse bone marrow and human monocyte cultures are not fully defined.…”