Project: Dissecting the mechanisms involved in macrophage differentiation of monocytes and their alterations in CMML
Monocytes are circulating blood leukocytes that migrate into tissues where they differentiate into morphological and functionally heterogeneous cells, including macrophages, myeloid dendritic cells, and osteoclasts. Their differentiation can be recapitulated ex vivo by incubation with cytokines, e.g. they differentiate into macrophages upon exposure to colony-stimulating factor-1 (M-CSF). We recently established that proper macrophagic differentiation of monocytes required both caspase and autophagy activation and pinpointed a novel and highly specific mechanism of caspase activation during this process. This may explain the limited number of cleaved substrates at sites different from those cleaved during apoptosis observed during monocyte differentiation. In this context, the main objectives of our project are to decipher this original mechanism of caspase activation, understand the specificity of cleavage and the role of the cleaved fragments and define the interplay between caspases and autophagy during M-CSF mediated monocyte differentiation. We expect to highlight a new mode of caspase activation in a non-apoptotic context, i.e. the physiological differentiation of monocytes into M2-like macrophages and more widely during M2-polarization of macrophages. This better characterization of caspase activation will also bring new insights in our understanding of M2-like macrophages generation especially implicated in the tumor growth. Finally, understanding these mechanisms of differentiation will allow us to better understand the pathophysiology of the chronic myelomonocytic leukemia (CMML) characterized by defect in monocyte differentiation.
Animal and cellular models
Human and mouse primary monocytes Human primary MDSCs Human primary CD34+ cells