Programmed cell removal by calreticulin in tissue homeostasis and cancer.
Macrophages are large white blood cells that are capable of strategically eliminating dying, damaged, and diseased cells within our tissues. We and others have previously found that target cells expressing high levels of Calreticulin, an “eat-me” signal, are readily susceptible to being cleared by macrophages. In this study, we demonstrate that activated macrophages are capable of secreting and labeling viable cells, with their own Calreticulin to mediate target cell elimination. These findings have broad potential implications for a variety of diseases and lead us towards better understanding how macrophages can be exploited for the development of new therapeutic strategies.
Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR. Importantly, we identified asialoglycans on the target cells to which CRT binds to regulate PrCR, and the availability of such CRT-binding sites on cancer cells correlated with the prognosis of patients in various malignancies. Our study reveals a general mechanism of target cell recognition by macrophages, which is the key for the removal of unwanted cells by PrCR in physiological and pathophysiological processes.