Figure 3.

IL-34 signaling pathways involved in macrophage differentiation and non-monocyte cells. A) Various stimuli, such as bacterial or viral infections, pro-inflammatory cytokines, DNA damage, or chemical molecules, modulate IL-34 expression. IL-34 binds to CSF-1R or to syndecan-1 receptors expressed at the cell surface of monocytes/macrophages. The binding of IL-34 to CSF-1R induces activation of CSF-1R through auto-phosphorylation of the different tyrosines present in the cytosolic domain of CSF-1R. Compared to CSF-1, IL-34 induces strong and transient activation of CSF-1R, as well as rapid downregulation of CSF-1R. These differences between the two cytokines imply differential activation of downstream signaling pathways that result in a diversity of macrophage biological processes such as differentiation, proliferation, survival, or migration. The binding of IL-34 to the chondroitin chains of syndecan-1 results in in vitro phosphorylations of the tyrosines Y708 and Y723 of CSF-1R, suggesting that the complex IL-34/syndecan-1 acts as a regulator of CSF-1R activity. Moreover, IL-34/syndecan-1 interaction regulates macrophage migration. B) IL-34 expression in the microenvironment of epithelial cells, fibroblasts and tumor cells can induce, via CD155, activation of the different signaling pathways implicated in biological functions such as cell proliferation, migration, survival, and cytokines. IL-34 also binds to RPTP-ζ, and controls inhibition of migration and proliferation of tumor cells lines such as glioblastoma U251.