Rôle de l'autophagie dans la signalisation, le trafic et les fonctions des récepteurs au fragment Fc des immunoglobulines dans les cellules myéloïdes

Immunoglobulin Fc receptors (Fc receptor) play a central role in immunity. They are expressed on the surface of several immune cells, such as myeloid cells. Most of these receptors are activator and upon binding of immune complexes, they are capable of mediating various effector functions: phagocytosis, antibody-dependent cytotoxicity, cytokine secretion and antigen presentation. These different functions enable immune cells to fight tumors and infections but have a deleterious effect in certain autoimmune diseases. The Fc receptor signaling cascade begins at the membrane. Once the receptor-ligand-complex has been internalized, this signaling continues in the endosomes: this is the concept of endosomal signaling. It has previously been demonstrated that this signaling via endosomes is necessary and indispensable for the effector functions of the FcyRI receptor, an activator receptor. It has also been described that the endocytosis pathway is interconnected with the autophagy pathway. Autophagy is a process of degradation and recycling of cytoplasmic constituents. This metabolic pathway responds to various signals, such as oxidative stress or infection. Given the importance of endosomal trafficking of Fc fragment receptors, and the close communication between endocytosis and autophagy, the aim of this study was to investigate the role of autophagy in Fc fragment receptor signaling, trafficking and function, particularly in monocytes and macrophages. In vitro, activation of Fc receptors by immune complexes induces the autophagy pathway via recruitment of the phosphatase Pp2a. The use of mice genetically modified for autophagy in myeloid cells has enabled further investigations: Atg5KO mice show suppressed autophagy, while RubcnKO mice show facilitated autophagy. Using bone marrow-derived cells from these mice, ex vivo, Fc receptor trafficking appeared altered when autophagy was modulated, but their signaling was unaffected and comparable to control mice. An initial transcriptome analysis of spleen phagocytic cells expressing CD64 and MertK showed an increased response to interferon gamma in RubcnKO cells. In contrast, a translation defect was demonstrated in Atg5KO cells, as well as a monocyte defect. A second transcriptome analysis, separating monocytes and macrophages, confirmed the predominant impact of Atg5 deletion in monocytes compared to macrophages. This monocyte alteration is characterized by an exacerbated inflammatory response, incomplete differentiation, slowed proliferation and reduced secretion of Cramp, which plays a role in mediating antibody-dependent cytotoxicity. Finally, in vivo, the effector function of Fc receptors was assessed using a model of B cell depletion in blood and spleen. Depletion of B lymphocytes in the blood was unaffected regardless of mouse genotype. However, it was less effective in mice with suppressed autophagy (Atg5KO), whereas it was improved in mice with facilitated autophagy (RubcnKO). Taken together, these results suggest an important role for autophagy following Fc receptor activation. Autophagy also appears to be necessary for the proper development of monocytes and macrophages and is required for their Fc receptor-mediated effector functions.