The affirmative response of the innate immune system to apoptotic cells

Abstract

Growing evidence exists for a new role for apoptotic cell recognition and clearance in immune homeostasis. Apoptotic cells at all stages, irrespective of membrane integrity, elicit a signature set of signaling events in responding phagocytes, both professional and non-professional. These signaling events are initiated by receptor-mediated recognition of apoptotic determinants, independently of species, cell type, or apoptotic stimulus. We propose that the ability of phagocytes to respond to apoptotic targets with a characteristic set of signaling events comprises a second distinct dimension of innate immunity, as opposed to the traditional innate discrimination of self vs. non-self. We further propose that a loss or abnormality of the signaling events elicited by apoptotic cells, as distinct from the actual clearance of those cells, may predispose to autoimmunity.

Figure 1

Discrete signaling events elicited within phagocytes by the recognition vs. engulfment of dead cells. The clearance of dead cells by phagocytes, both professional and non-professional, is associated with a number of early signaling events. These signaling events can be broken up into: (A) those mediated by the recognition of apoptotic vs. necrotic corpses, and (B) those mediated by their engulfment via a common phagocytic machinery. (A) Receptor-mediated discrimination of apoptotic vs. necrotic corpses elicits directionally opposite responses in pro-inflammatory transcription (denoted here as NFκB-dependent transcriptional activity) and the activity of the signaling kinases ERK1/2, JNK1/2 and p38. Apoptotic cells, at all stages, irrespective of the integrity of the plasma membrane, initiate identical signaling events. (B) Signaling events linked to the engulfment of apoptotic and necrotic cells are directionally similar and lead to the activation of Akt and its downstream targets, GSK3β and BAD. Latex particles, which are taken up in a receptor-independent manner, elicit no recognition-dependent signaling events, but, like dead cells, activate Akt via their engulfment.

Figure 2

Two distinct criteria of innate immune recognition. Innate immune responsiveness is an integrated function of two independent criteria of immune recognition. One criterion is the well-appreciated discrimination along a self vs. other (non-self) axis. The second reflects the discrimination between viable and dead (particularly apoptotic) cells. These two distinct criteria of recognition are represented here along orthogonal axes. Whereas recognition of non-self determinants engages a signal transduction pathway linked to inflammatory outcomes, apoptotic recognition triggers distinct signaling events that result in antagonistic, anti-inflammatory outcomes. The placement of necrotic cells in this schema is less obvious. At least with regard to inflammatory responses, necrotic cells are more like pathogenic invaders than apoptotic cells, although their ability to elicit inflammatory responses tends to be modest at best (10,13).

Figure 3

Exposure to apoptotic cells induces multiple signaling events that contribute to immune homeostasis. (A) The interaction of phagocytes with apoptotic cells results in a number of signaling events that are dependent upon both receptor-mediated recognition and engulfment of the apoptotic target (summarized in Figure 1). Among the signaling events induced by apoptotic cells, we speculate that some play a critical role in maintaining self-tolerance and preventing autoimmunity. (B) 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. The role of antigenic persistence is less clear, since apoptotic cells, at all stages, irrespective of membrane integrity, elicit identical signaling events. Alternatively, inherited or acquired abnormalities within the tolerogenic signaling pathways that are induced by apoptotic cells may constitute a predisposing background for the development of autoimmunity.