GM-CSF-Dependent Inflammatory Pathways

Abstract

Pre-clinical models and clinical trials demonstrate that targeting the action of the cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), can be efficacious in inflammation/autoimmunity reinforcing the importance of understanding how GM-CSF functions; a significant GM-CSF-responding cell in this context is likely to be the monocyte. This article summarizes critically the literature on the downstream cellular pathways regulating GM-CSF interaction with monocytes (and macrophages), highlighting some contentious issues, and conclusions surrounding this biology. It also suggests future directions which could be undertaken so as to more fully understand this aspect of GM-CSF biology. Given the focus of this collection of articles on monocytes, the following discussion in general will be limited to this population or to its more mature progeny, the macrophage, even though GM-CSF biology is broader than this.

Keywords: CCL17; IRF4; cell survival; inflammation; pain; polarization.

Figure 1

GM-CSF and monocytes/macrophages in inflammation. Depicted are some potential local and systemic actions of GM-CSF on monocyte/macrophage populations during an inflammatory reaction. Whether particular actions operate are currently debated and are likely to depend on the nature of the inflammatory reaction and the levels of GM-CSF attained from hemopoietic (e.g., lymphocyte) and non-hemopoietic (e.g., fibroblast) cell populations. Locally GM-CSF can act in a concentration—dependent manner on target cells (resident macrophages and/or blood-derived monocytes) to promote their survival and/or polarization/differentiation; the latter cell target can give rise to MoDCs. Their polarization/differentiation can be characterized by the production of proinflammatory mediators such as cytokines (e.g., IL-1β, TNF), proteases, reactive oxygen species (ROS), etc. One interesting pathway (zoomed), which seems to be important for GM-CSF-dependent inflammation and associated pain, leads to CCL17 production via JMJD3 and IRF4. GM-CSF can also act systemically in the blood and/or bone marrow, either directly or indirectly () via its cellular targets in the tissue, leading to migration/mobilization of monocytes or their precursors and/or monocyte development from these precursors (myelopoiesis) (). MoDC, monocyte-derived DC.