Determining the effector response to cell death

Abstract

Cell death occurs when a pathogen invades a host organism or the organism is subjected to sterile injury. Thus, cell death is often closely associated with the induction of an immune response. Furthermore, cell death can occur as a consequence of the immune response and precedes the tissue renewal and repair responses that are initiated by innate immune cells during resolution of an immune response. Beyond immunity, cell death is required for development, morphogenesis and homeostasis. How can such a ubiquitous event as cell death trigger such a wide range of context-specific effector responses? Dying cells are sensed by innate immune cells using specialized receptors and phagocytosed through a process termed efferocytosis. Here, we outline a general principle whereby signals within the dead cell as well as the environment are integrated by specific efferocytes to define the appropriate effector response.

Figure 1 |. Schematic representation of the proposed code of cell death.

According to a reductionist theory (top), there is a one-to-one relationship between the type of cell death and the effector function. As an example, non-inflammatory cell death is associated with physiological resolution and repair responses, whereas inflammatory cell death is associated with the control of injury and infection but can result in pathologies associated with defective resolution or repair. By contrast, the emergent theory (bottom) that we outline in this Review takes into account the variety of cell death types, the multitude of accompanying environmental signals and their integration by different efferocytes for the execution of specific effector responses. As such, the same cell death modality can result in distinct effector functions, depending on the specificity of environmental signals and the efferocyte. For simplicity, only three types of cell death, environment, efferocyte and effector response are shown here, but in the broader contexts of development, homeostasis and repair, there are a large set of spatially and temporally distinct combinations resulting in different effector responses.

Figure 2 |. The role of the efferocyte.

Three distinct scenarios represent possible relationships between cell death, efferocytes and effector responses. a | Recognition of a particular type of dead cell by a dedicated efferocyte results in a specialized effector function. b,c | Alternatively, the recognition of dead cells could give rise to multiple and distinct effector functions. This could result from the recognition of dead cells by different efferocytes (b) or from divergent effector responses being executed by the same efferocyte (c).

Figure 3 |. The role of the dying cell.

The information provided by the dying cell can be contained in the type of cell death modality, the number of dead cells and the identity of the dead cells.

Figure 4 |. The role of the environment.

The tissue environment can contribute to determining the effector response of the efferocyte either directly through specialized cytokines that are uniquely present in an environment, or through unique tissue-specific epigenetic and/or transcriptional changes or unique metabolic functions associated with a specific environment, or indirectly by influencing the type of cell death, which in turn can affect the effector response.