The P2Y6-AMPK Pathway Triggers Autophagy during CSF-1-Induced Human Monocyte Differentiation and Is a Potential Target in CMML

Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacological and genetic evidence indicate that autophagy plays pleiotropic functions in cellular homeostasis, development, survival and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by M-CSF. We have previously shown, using pharmacological inhibitors, siRNA approaches and Atg7^-/- mice, that autophagy initiated by ULK1 is required for proper CSF-1-driven differentiation of human and murine monocytes. We have also unraveled a role for autophagy in macrophage acquisition of phagocytic functions. Here, we determine that the CaMKKb-AMPKa1-ULK1 pathway is required for CSF-1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2Y6 to the induction of autophagy, and we decipher the signalling network that links the CSF-1 receptor to P2Y6-mediated autophagy and monocyte differentiation. Importantly, we show that the physiological P2Y6 ligand UDP and the specific P2Y6 agonist MRS2693 restore normal monocyte differentiation through re-induction of autophagy in primary myeloid cells from chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for P2Y6-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML.