The molecular legacy of apoptosis in transplantation

Transplanted organs have to cope with diverse immunologic and metabolic stressors that augment the percentage of stressed and dying cells. Cell death, whether apoptotic or necrotic, is crucial in various transplantation-associated conditions. Necrosis, a proinflammatory type of cell death classically considered as accidental, is increasingly recognized as a highly controlled death program. Apoptosis, the classical programmed cell death mode program, is tightly orchestrated and culminates in the activation of caspases. Apoptosis was classically regarded as a silent form of cell death, but mounting evidence indicates that apoptotic cells "don't go silently" and leave a heritage to the local microenvironment. This apoptotic legacy, embedded within the effector phase of apoptosis, is aimed, at least in part, at controlling leukocyte trafficking and fostering tissue remodeling at sites of apoptotic cell deletion and can promote maladaptive remodeling pathways of importance for obliterative vascular remodeling. Moreover, apoptotic cells can transfer bioactive molecules by the release of apoptotic membrane vesicles that, in turn, shapes the phenotype and functions of immune cells. In this review, we summarize recent data highlighting the importance of apoptosis-associated intercellular communication networks in the regulation of allograft remodeling and immune responses in transplantation.