Abstract
Macrophages engulf and destroy pathogens (phagocytosis) and apoptotic cells (efferocytosis), and can subsequently initiate adaptive immune responses by presenting antigens derived from engulfed materials. Both phagocytosis and efferocytosis share a common degradative pathway in which the target is engulfed into a membrane-bound vesicle, respectively, termed the phagosome and efferosome, where they are degraded by sequential fusion with endosomes and lysosomes. Despite this shared maturation pathway, macrophages are immunogenic following phagocytosis but not efferocytosis, indicating that differential processing or trafficking of antigens must occur. Mass spectrometry and immunofluorescence microscopy of efferosomes and phagosomes in macrophages demonstrated that efferosomes lacked the proteins required for antigen presentation and instead recruited the recycling regulator Rab17. As a result, degraded materials from efferosomes bypassed the MHC class II loading compartment via the recycling endosome – a process not observed in phagosomes. Combined, these results indicate that macrophages prevent presentation of apoptotic cell-derived antigens by preferentially trafficking efferocytosed, but not phagocytosed, materials away from the MHC class II loading compartment via the recycling endosome pathway.
Highlights
Clearance of apoptotic cells in a timely and efficient manner is essential for preventing the induction of inflammation and the maintenance of homeostasis.[1,2] The process of apoptotic cell clearance, termed efferocytosis, is performed by both professional phagocytes such as macrophages[3,4] and dendritic cells,[5,6] and by some non-phagocytic cell types such as epithelial cells.[7,8] Apoptotic cells that are not cleared undergo secondary necrosis, driving inflammation and autoimmunity through the release of self-antigens and proinflammatory intracellular contents into the extracellular milieu.[9]
While a number of ligands, mediators and receptors that regulate efferocytosis have been identified and characterized,[10] little is known of the maturation process that degrades efferocytosed cells, or the processes that determine the ultimate fate of degraded apoptotic cells
To test whether apoptotic cells were trafficked through a novel maturation pathway in professional antigenpresenting cells (pAPC), we tracked the recruitment of ectopically expressed Rab5-GFP and Rab7RFP in J774.2 macrophages engaged in phagocytosis (Figures 1a and c) or efferocytosis (Figures 1b and d) of
Summary
Clearance of apoptotic cells in a timely and efficient manner is essential for preventing the induction of inflammation and the maintenance of homeostasis.[1,2] The process of apoptotic cell clearance, termed efferocytosis, is performed by both professional phagocytes such as macrophages[3,4] and dendritic cells,[5,6] and by some non-phagocytic cell types such as epithelial cells.[7,8] Apoptotic cells that are not cleared undergo secondary necrosis, driving inflammation and autoimmunity through the release of self-antigens and proinflammatory intracellular contents into the extracellular milieu.[9]. Within minutes of engulfment Rab[5] is exchanged for Rab[7], upon which Rab[7] mediates the fusion of late endosomes and lysosomes with the phagosome or efferosome While this latter portion of the efferocytosis pathway has not been fully characterized, it is believed to proceed in a manner identical to that of phagocytosis. Using mass spectrometry and fluorescence microscopy, we identified a Rab17-dependent maturation process that mediates the transfer of degraded apoptotic cell materials to the recycling endosome and away from the MHC class II loading compartment, thereby preventing apoptotic cell-derived materials from intersecting the macrophage antigen presentation machinery
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