Cracking the Cell Death Code

Abstract

Cell death is an invariant feature throughout our life span, starting with extensive scheduled cell death during morphogenesis and continuing with death under homeostasis in adult tissues. Additionally, cells become victims of accidental, unscheduled death following injury and infection. Cell death in each of these occasions triggers specific and specialized responses in the living cells that surround them or are attracted to the dying/dead cells. These responses sculpt tissues during morphogenesis, replenish lost cells in homeostasis to maintain tissue/system function, and repair damaged tissues after injury. Wherein lies the information that sets in motion the cascade of effector responses culminating in remodeling, renewal, or repair? Here, we attempt to provide a framework for thinking about cell death in terms of the specific effector responses that accompanies various modalities of cell death. We also propose an integrated threefold "cell death code" consisting of information intrinsic to the dying/dead cell, the surroundings of the dying cell, and the identity of the responder.

Figure 1.

Classification of cell death based on associated outcomes. Cell death associated with the creation or elimination of a function is defined as type I. An example is represented by the cell death associated with embryonic and perinatal brain development. Type II cell death defines the demise of cells associated with homeostatic renewal of tissues in adulthood. This is exemplified by cell death associated with replenishment of adult organs such as the intestine. Unscheduled cell death is defined as type III cell death and is associated with inflammation, immunity (in case of infection), and tissue repair. This is represented in the context of an arm injury.

Figure 2.

Invariant and unique molecular patterns associated with cell death. Phosphatidylserine ([PtdSer], indicated as green textured line) is a phospholipid found in all eukaryotic cells this is asymmetrically distributed in the plasma membrane of alive cells. Although PtdSer is enriched in the inner leaflet of live cells, it becomes invariantly exposed on the cell surface of apoptotic cells. Whether PtdSer is an universal molecular pattern of all cell death modalities remains unknown. Other molecular patterns of cell death are characterized by their distinct subcellular localization in live cells before their release when cells die. For example, calreticulin is found in the endoplasmic reticulum and HMGB1 in the nucleus. In contrast, ATP localization is less restricted, being present in mitochondria, the cytosol, and the nucleus. Molecular patterns associated with cell death can also be induced on specific cell death modalities. Activation of the inflammasome during pyroptosis leads to the production of interleukin (IL)-1β and IL-18.

Figure 3.

Environmental signals and cell death. A panoply of signals, spanning from hormones and cytokines to neurotransmitters, metabolites, and beyond can coexist with dead cells. The processing of cell death recognition together with distinct environmental signals contributes to the specification of the outcomes of cell death. ECM, Extracellular matrix.

Figure 4.

Who cares about dead cells? An array of different cells are endowed with the capacity to efferocytose or sense dead cells. The identity of the cellular sensors involved in the diverse tissues and contexts in which cells can die in part dictates the specific outcomes of the efferocytes that respond to dead cells.