Abstract
CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. IL-34 promotes the differentiation and survival of monocytes, macrophages and osteoclasts, as CSF-1 does. However, IL-34 binds other receptors, suggesting that differences exist in the effect of both cytokines. In the present study, we compared the differentiation and polarization abilities of human primary monocytes in response to CSF-1 or IL-34. CSF-1R engagement by one or the other ligands leads to AKT and caspase activation and autophagy induction through expression and activation of AMPK and ULK1. As no differences were detected on monocyte differentiation, we investigated the effect of CSF-1 and IL-34 on macrophage polarization into the M1 or M2 phenotype. We highlighted a striking increase in IL-10 and CCL17 secretion in M1 and M2 macrophages derived from IL-34 stimulated monocytes, respectively, compared to CSF-1 stimulated monocytes. Variations in the secretome induced by CSF-1 or IL-34 may account for their different ability to polarize naïve T cells into Th1 cells. In conclusion, our findings indicate that CSF-1 and IL-34 exhibit the same ability to induce human monocyte differentiation but may have a different ability to polarize macrophages.
Highlights
colony-stimulating factor-1 (CSF-1) and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes
Downstream signaling pathways activated by CSF-1R upon ligand binding include PI3K-AKT and AMPK pathways, which are implicated in the respective activation of caspases and autophagy, two key processes required for CSF-1-induced macrophage differentiation[5]
The results described above indicate that CSF-1 and lL-34-mediated intracellular signaling pathways, including auto-phosphorylation of the CSF-1R, activation of AKT, ERK 1/2, AMPK and ULK1 and induction of caspase activities and autophagy are similar in human primary monocytes induced to differentiate into macrophages, suggesting that the effects of lL-34 are mediated via the CSF1-R
Summary
CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. CSF-1R engagement by one or the other ligands leads to AKT and caspase activation and autophagy induction through expression and activation of AMPK and ULK1. Downstream signaling pathways activated by CSF-1R upon ligand binding include PI3K-AKT and AMPK pathways, which are implicated in the respective activation of caspases and autophagy, two key processes required for CSF-1-induced macrophage differentiation[5]. IL-34 has been recently identified as the second ligand for CSF-1R through comprehensive proteomic analyses[11] It lacks appreciable similarity with CSF-1 or any other proteins, IL-34 tightly binds to CSF-1R and promotes the differentiation, proliferation and survival of monocytes, macrophages and osteoclasts as CSF-1 does[12,13]. We report that IL-34 and CSF-1 macrophages display a different polarization potential when polarized by pro or anti-inflammatory stimulus, since we found some differences in the mRNA and protein expression profiles of some cytokines/chemokines in CSF-1 and IL-34 differentiated cells polarized into the M1 or M2 phenotype
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