Exposure of macrophages to apoptotic cells induces multiple signaling events that contribute to immune homeostasis
A, the interaction of macrophages with apoptotic cells results in a number of signaling events. As shown in this study, apoptotic cells inhibit ERK1/2 but activate JNK1/2 and p38. We have previously shown that apoptotic cells activate the anti-apoptotic kinase Akt (17) and inhibit activation of proinflammatory transcription factors (5, 10). Recognition of apoptotic cells also leads to cytoskeletal changes that facilitate phagocytosis of apoptotic cells. Among the signaling events induced by apoptotic cells, we speculate that some play a critical role in maintaining self-tolerance by regulating the presentation of apoptotic cell-derived self-antigens in the context of major histocompatibility complex molecules and other T cell-stimulatory molecules. B, the signaling events induced by exposure to apoptotic cells may play a role in preventing autoimmunity. According to the model we suggest, loss of self-tolerance, with resultant autoimmunity, may occur through one of two fundamental mechanisms. First, impaired clearance of apoptotic cells, as may occur through targeted deletion of relevant genes, results in a decreased interaction of apoptotic cells with phagocytes and therefore a decreased amount of tolerogenic signals within the phagocyte. However, as shown in this study, persistence of apoptotic cells, with the loss of membrane integrity, does not in and of itself alter the nature of the signaling events induced in response to apoptotic cell recognition, merely its intensity, and therefore apoptotic cell persistence is unlikely itself to be the cause of autoimmunity. Alternatively, inherited or acquired abnormalities within the tolerogenic signaling pathways themselves, that are induced by apoptotic cells, may constitute a predisposing background for the development of autoimmunity.