Gut check: dead cell samples leads to tolerant examples

Recent studies have garnered attention and appreciation for the role that phagocytes of the innate immune system play in the clearance of dying cells, a process termed efferocytosis. The sensing, recognition, and removal of cellular corpses is a reoccurring event throughout the lifetime of organisms, and considering the billions of cells that undergo apoptosis daily and the rarity of observing an uncleared apoptotic cell under normal physiological conditions, one must truly admire the efficiency with which phagocytes perform their duties.¹ The clearance of dead cells is designed to be a tolerated mechanism, as apoptosis is a common, genetically programmed process designed to sculpt, control and aid the body in its development and survival.² Thus, efferocytosis must occur in an ‘immunologically silent’ manner, so as to not inappropriately alert the immune system during times of development, cellular homeostasis, and stress.³

However, not all tissue-resident phagocytes are created equally when it comes to efferocytosis. Words such as ‘phagocytes’ and ‘tissue’ are broad terms that minimize the uniqueness and specificity that underlies each cellular subset within individual tissue environments. Phagocytes within the skin do not encounter the same challenges as phagocytes in the gut, and different types of phagocytes within the same tissue are evolutionarily poised to carry out certain distinct functions.⁴ Cummings et al. develop an exciting mouse model capable of inducing tissue-specific apoptosis and to track the fate of the phagocytes that efferocytose these corpses. This novel mouse model, termed the VDTR mouse, expresses a transgenic diphtheria toxin receptor fused to eGFP under the control of the epithelial cell specific villin promoter. After administration of a non-inflammatory dose of diphtheria toxin, the intestinal epithelial cells (IECs) in the small intestine of the VDTR mouse undergo apoptosis, as determined by caspase-3 cleavage. As the apoptotic cells express eGFP, their fate and influence can be followed with the phagocytic subsets that engulf and process them.⁵

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