Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

Abstract

Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions.

DOI: http://dx.doi.org/10.7554/eLife.01004.001

eLife digest

The tissues of developing organisms can be shaped by apoptosis, a form of regulated cell killing. Although this process can occur in individual cells, apoptotic signals may also dictate the ‘communal death’ of many cells simultaneously. This occurs frequently in animal development: in human fetuses, for example, cells in the hand are directed to die to remove webbing between the fingers.

Apoptosis has been thought to resemble a form of silent suicide by cells, but more recent work suggests that apoptotic cells can also transmit signals. Now, Pérez-Garijo et al. find that these cells can stimulate other cells to die in both fruit flies and mice.

In fruit flies, apoptosis is activated by proteins known as Grim, Hid and Reaper. To explore whether apoptotic cells could communicate with other cells, Pérez-Garijo et al. created ‘undead’ cells in which one of these proteins was turned on, but other downstream proteins (that are responsible for the cellular execution phase of apoptosis) had been turned off: these cells were undergoing apoptosis, but could not complete the process and die.

Strikingly, undead cells in the posterior (back) region of the wing imaginal disc—the tissue in the larva that gives rise to the wing in the adult fruit fly—could trigger apoptosis in cells in the anterior (front) half. Pérez-Garijo et al. found that the JNK pathway activated apoptosis in anterior cells. In fruit flies, the Eiger protein turns on this pathway; when Eiger was absent from posterior cells in the wing imaginal disc, apoptosis in anterior cells ceased, indicating that Eiger might signal at long range.

Eiger is related to a protein called TNF that has been implicated in cycles of destruction and renewal of hair follicles in mice. Pérez-Garijo et al. found that TNF is produced by apoptotic cells in hair follicles, and that blocking TNF inhibits the death of other cells in the same cohort: this suggests that a common mechanism could regulate the communal death of cells in flies and mammals. These studies therefore shed light on a conserved pathway in the modulation of tissue development.

DOI: http://dx.doi.org/10.7554/eLife.01004.002