Abstract
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.
Highlights
N-Glycans O-Glycans Sulfated glycansMFI–400 BgMan[1] Man[2] Man[3] Man[4] Man[5] Man[6] Man[7] Man[8] MaMna9n9-KLH[ManM9]a4n9-PAAAGOR ASOR OSMOG PSM ChDo3n3drCohitoinnAdCrhooitinndBroitin C Mφ Neutrophils cBone marrow neutrophils Ctrl rCRT PHA-L MFI e HL60 f SW620
In agreement with our previous findings using this animal model, we found after thioglycollate induced peritonitis, the Bcl2-expressing neutrophils were resistant to apoptosis but were removed from the peritoneum with the same temporal dynamics as WT neutrophils undergoing cell death (Fig. 1a, b and Supplementary Fig. 1b)
These data indicate that aged neutrophils are programmed to be removed through programmed cell removal (PrCR); recognition of such target cells by macrophages is independent of their cell death
Summary
–400 BgMan[1] Man[2] Man[3] Man[4] Man[5] Man[6] Man[7] Man[8] MaMna9n9-KLH[ManM9]a4n9-PAAAGOR ASOR OSM
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