Of Tingible Bodies and Starry Skies: Control of Normal and Malignant Tissues Through Apoptotic Cell-Dependent Communication (ACDC).

Apoptosis, the original regulated cell death programme, is an established controller of cell populations in all tissues. The hub of the apoptosis machinery, the caspase cascade, mediates the cleavage of hundreds of protein substrates to ultimately effect disabling and dismantling of cells, deleting them in a cell-autonomous fashion that is well understood. Of lesser renown are the intercellular communicative properties of apoptotic cells which, as burgeoning evidence indicates, compound the signalling processes that culminate in the famously speedy, and most commonly non-phlogistic, phagocytic clearance of dying/dead cells and their fragments (efferocytosis) by macrophages and other efferocytes. Here, we discuss more broadly the curious variety of instructive intercellular signals that apoptotic cells can deploy in order to reprogramme their living neighbours, be they close or distant, efferocytes or not. We review the literature, and we consider conceptually the potential of such non-cell-autonomous, apoptotic cell-dependent communication (ACDC) mechanisms to profoundly impact cell populations in health and disease. We illustrate our discourse firstly with the biology of lymphoid germinal centres (GC) and their constituent efferocytic, 'tingible body' macrophages, and secondly with the pathology of malignancies in which counterpart efferocytic, 'starry sky' macrophages feature prominently. In conclusion, we suggest several key avenues in ACDC research.