GM-CSF in inflammation

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.

Figure 1.

A GM-CSF–IRF4–CCL17 pathway in inflammation and pain. During an inflammatory reaction, GM-CSF, generated following TNF-dependent and -independent stimulation, induces in monocytes and macrophages the formation of CCL17 through a signaling pathway involving the induction of the transcription factor, IRF4, via the activity of the demethylase, JMJD3 (Achuthan et al., 2016). By unknown mechanisms, secreted CCL17 can result in inflammation and tissue remodeling, for example, in arthritic joints, as well as drive the development of pain; the latter response appears to require a contribution from an eicosanoid (for example, PGE₂). GM-CSF–IRF4 signaling can in addition control expression in monocytes and macrophages of other potential proinflammatory effectors, such as surface-bound MHC class II. GM-CSF and TNF, potentially produced by numerous cell types (not shown) in response to various stimuli, including damage-associated molecular patterns (DAMPs), can engage in a cytokine loop, thus potentially linking TNF biology to the GM-CSF–CCL17 pathway (Cook et al., 2018b).

Figure 2.

GM-CSF and control of target cell numbers and function in inflammation. During an inflammatory reaction, it is likely that the major actions of endogenous GM-CSF are in the inflamed tissue in which GM-CSF can act in a concentration-dependent manner on resident macrophages and/or migrated monocytes, neutrophils, and eosinophils to promote their survival and/or modify their differentiation/polarization, such as the maturation of the monocytes into MoDCs and macrophages. Myeloid cell trafficking in (or out) of the inflamed tissue may also be under GM-CSF control. The cell differentiation/polarization can be characterized by the production of proinflammatory mediators such as cytokines, chemokines, proteases, reactive oxygen species, etc. (not shown); monocyte/macrophages may also proliferate (not shown). The tissue-derived GM-CSF may also act systemically in the blood and/or bone marrow, either directly or indirectly via its cellular targets in the tissue (not shown), to activate myeloid cells in the blood before their migration into the inflamed tissue and contribute to this migration; it may contribute as well as to myeloid mobilization/cell migration from the bone marrow, where it may also promote lineage-specific myelopoiesis from progenitor cells. Whether the particular highlighted actions of GM-CSF operate is currently debated and is likely to depend on the nature of the inflammatory reaction and the levels of GM-CSF attained from hemopoietic (e.g., lymphocyte) and nonhemopoietic (e.g., fibroblast) cell populations. GM-CSF targeting (depicted by inhibitory lines) could occur locally in the inflamed tissue and systemically to control disease.