The discovery of the immunomodulato

The discovery of the immunomodulatory activity of apoptotic cells on macrophages nearly 20 years ago transformed our view of efferocytosis from a simple garbage disposal process to one capable of actively shaping immune responses and influencing tissue restorative programs. This paradigm shift has led to promising new therapeutic avenues built on manipulating efferocytosis-related processes, as evidenced by the ongoing trials of anti-PtdSer antibodies in several clinical settings (125, 126). The efferocytosis mechanisms highlighted here illustrate the ability of macrophages to engage specific molecular pathways that control both phagocytosis and immune signaling. This linkage supports the idea that the process of dead cell clearance is not simply an end unto itself, but rather that the efferocytosis process provides key physiologic status information regarding cell death and tissue health to the immune system via macrophages (and other phagocytes). Finally, it is important to note that while efferocytosis signaling is often framed as a chronological three-step process (Figure 1), physiologic efferocytosis by macrophages almost certainly involves the simultaneous integration of many different efferocytosis signaling processes. As such, understanding how the spatiotemporal dynamics and potential synergistic relationships of these different signaling pathways affect cell clearance and immunity stands as an important, albeit very challenging, area for future studies. Considering the ubiquity of cell death during inflammation and the inherent signaling complexities of inflamed tissues, major mechanistic advances in this area will likely require new experimental approaches to tease apart the precise immunomodulatory roles of dead cell-derived signals.