Specific Recognition of Apoptotic Cells Reveals a Ubiquitous and Unconventional Innate Immunity

Abstract

The purpose of physiological cell death is the noninflammatory clearance of cells that have become inappropriate or nonfunctional. Consistent with this function, the recognition of apoptotic cells by professional phagocytes, including macrophages and dendritic cells, triggers a set of potent anti-inflammatory responses manifest on multiple levels. The immediate-early inhibition of proinflammatory cytokine gene transcription in the phagocyte is a proximate consequence of recognition of the apoptotic corpse, independent of subsequent engulfment and soluble factor involvement. Here, we show that recognition is linked to a characteristic signature of responses, including MAPK signaling events and the ablation of proinflammatory transcription and cytokine secretion. Specific recognition and response occurs without regard to the origin (species, tissue type, or suicidal stimulus) of the apoptotic cell and does not involve Toll-like receptor signaling. These features mark this as an innate immunity fundamentally distinct from the discrimination of "self" versus "other" considered to be the hallmark of conventional immunity. This profound unconventional innate immune discrimination of effete from live cells is as ubiquitous as apoptotic cell death itself, manifest by professional and nonprofessional phagocytes and nonphagocytic cell types alike. Innate apoptotic immunity provides an intrinsic anti-inflammatory circuit that attenuates proinflammatory responses dynamically and may act systemically as a powerful physiological regulator of immunity.

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

“…This similarity in engulfment kinetics between the two types of beads suggests a common rate-limiting step for internalization of the particle, most likely related to the cytoskeletal rearrangements necessary for phagocytic cup formation. Previous studies have also shown that apoptotic recognition can be dissociated from the engulfment step [5,25].…”

“…Phagocytosis is also a critical physiological process for tissue remodeling which removes apoptotic or aged cells in a regulated manner in the absence of inflammation [4]. Specific recognition of the apoptotic cell by the phagocyte occurs without regard to the species or tissue origin of the target or the nature of the apoptotic stimulus and can occur without the involvement of soluble factors [5].…”

Exploiting death: apoptotic immunity in microbial pathogenesis

“…Indeed, non-phagocytic cells recognize and respond to apoptotic corpses as well as phagocytic responders. 5,10 The apoptotic suppression of inflammation is exerted principally on the level of transcription, 5 and involves both the repression of the expression of genes encoding pro-inflammatory cytokines (such as tumor necrosis factor-α (TNFα) and interleukin (IL)-6), and the induction of gene expression for anti-inflammatory cytokines (such as IL-10). Primary elements of this extensive repertoire are listed in Box 1.…”

“…In contrast to its role in engulfment, 4 PS is not a determinant for the recognition-dependent initiation of IAI. 10,11 The cell surface determinant(s) involved in initiating IAI are not masked by annexin V, rather, they are protease-sensitive. 12 In addition, they are evolutionarily conserved, resident in all cells prior to cell death, and become surface-exposed (and susceptible to proteolytic digestion) during the process of apoptosis.…”

“…5,10 These transcriptional effects include the repression of expression of some genes, and the induction of expression of others (see Table). Additional transcriptional and other responses (e.g., the induction of TGFβ expression 13 ; Pattabiraman et al, unpublished Arg-II 73,75 ; Pattabiraman et al, unpublished delineated in Figure 1, and the glycolytic enzyme molecules that are externalized apoptotically are indicated.…”