In summary, I have assessed the early and late steps of efferosomes maturation in the mammalian system and compared these to the equivalent stages in phagosome
maturation. I determined that the early maturation stages appear to be identical between efferocytosis and phagocytosis, with Rab5 recruited early after internalization and then replaced with Rab7 and fusion with late endosomes/lysosomes at later time points. This indicates that efferosomes should undergo acidification with the subsequent activation in proteases and other degradative enzymes to process apoptotic cells51, although I was not able to test this directly in this thesis. Mass spectrometry analysis of efferosomes and phagosomes at the phagolysosome stage of maturation identified several interesting
differences between phagosomes and lysosomes, potentially identifying the mechanism by which efferocytic cargos induce the opposite immune response as do phagocytic cargos. For example, different vesicular trafficking mediated by Rab17 and Rab45 may keep efferosome-derived antigens from the antigen-loading compartment in macrophages by directing these antigens to recycling endosomes. In contrast, phagosomes had
abundant MHC II and directly interacted with the Golgi trafficking regulators Rab6b, PIK4 and GIMD1, indicating the phagosome was receiving MHC II directly from the Golgi network, perhaps for efficient loading of pathogen-derived antigens onto MHC II. Lastly, MAP kinase regulators accumulated on efferosomes and phagosomes in a pattern suggesting that MAP Kinase activity and NF-κB activation would occur on phagosomes but be impaired on efferosomes. These findings will lead to future studies which will seek to validate the mass spectrometry observations, and to characterize the roles of these proteins in mediating the differential immune responses following efferocytosis and phagocytosis.
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