Colony-Stimulating Factor-1 Receptor in the Polarization of Macrophages: A Target for Turning Bad to Good Ones?

Abstract

Macrophages, which are found in all tissues, are an essential component of the innate immune system, and they play important roles in host defense, inflammation, autoimmune diseases as well as cancer. Functionally, macrophages are classified into two types: classically-activated M1 macrophages and alternatively-activated M2 macrophages. The M1 macrophages typically produce high levels of proinflammatory cytokines and chemokines, whereas M2 macrophages show an efficient phagocytic and scavenging activity. Because the phenotypes of polarized M1 and M2 macrophages can be induced, and reversed to some extent, by various signals, different phases of many diseases are associated with dynamic changes in the balance between M1 and M2 macrophages. The colony-stimulating factor 1 receptor (CSF-1R), a class III receptor tyrosine kinase, sustains the survival, proliferation and differentiation of monocytes and macrophages. Drugging CSF-1R may be the only way to target macrophages within a pathological context. However, CSF-1R-dependent signals may be either positive or detrimental depending on the disease and even on the phase of disease. The role of CSF-1R and its ligands, the colony-stimulating factor-1 and interleukin-34, in macrophages with respect to the pathogenesis of several inflammatory or neoplastic diseases has been reviewed previously. This review will focus specifically on evidences obtained about the role of CSF-1R in macrophage polarization in the context of physiological as well as pathological conditions including inflammation and cancer. The possibility to target CSF-1R, using the several inhibitors already available, for the treatment of inflammatory diseases as well as cancer will be also discussed.

Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway

“…Moreover, increased macrophage numbers may, with few exceptions, exacerbate inflammatory diseases and enhance cancer progression. 29 In this work, we identified a new pathway, SFK-FAK>CSF-1R, relevant for FNinduced macrophage migration. To strengthen our results, we used two different murine cell lines, one dependent on and one independent of CSF-1, as well as primary human macrophages.…”

“…This result points to a possibly wider role of this phenomenon in other CSF-1R-expressing cells including dendritic or tumor cells. 29,38 Different mechanisms are involved in the transactivation of RTK by integrin ligands. 11 In particular, kinases and adaptor molecules may be involved in the cross-talk between integrins and RTK.…”

The roles of CSFs on the functional polarization of tumor‐associated macrophages

“…The antitumor impact of neutralizing the M‐CSF/CD115 axis has been reported in numerous preclinical models of tumor development, using either chemical compounds that specifically inhibit the tyrosine kinase activity of CD115 or neutralizing anti‐CD115 or anti‐M‐CSF monoclonal antibodies (mAbs). These molecules induce a strong reduction in the number of infiltrating macrophages in mice models of tumor development . As an example, blocking CD115 with the neutralizing mAb RG1755 reduces the density of TAM and increases the recruitment of CD8 + T cells .…”

Activated Microglia in the Brain: Mitochondrial and Cell Membrane-Associated Targets for Positron Emission Tomography

“…For immunological approaches, such polarization of the functionality of microglia corresponds to the actions of the subsets of T helper cells (CD4 cells), Th1 and Th2 lymphocytes releasing the respective Th1-type and Th2-type cytokines as pro-inflammatory or anti-inflammatory response [10] [15] [16].…”

“…Microglia accounts for 5% -10% of total glia cells of the human brain [10] [16] [17] and up to 20% in other mammalian species [18] [19] with lower percentage in the cortex and higher in corpus callosum. 30% -50% of cells in glioma are microglial cells; and glioma and astrocytoma are the most common brain tumors [20].…”