Abstract
The removal of unwanted or damaged cells by phagocytes is achieved via a finely regulated cleaning process called efferocytosis. To characterize the mechanisms through which phagocytes control the intake of apoptotic cells, we investigated how the phagocyte’s appetite for engulfed cells may be coordinated by RhoA and Rac1 in the phagocytic cup. We used FRET biosensors to visualize the spatiotemporal dynamics of Rho-family GTPases, and found that RhoA, which is known to be downregulated during phagocytosis, was transiently upregulated at the phagocytic cup immediately prior to ingestion. Conversely, Rac1 was upregulated during the engulfment process and then downregulated prior to phagosomal maturation. Moreover, disturbance of the dynamic activities of RhoA led to uncontrolled engulfment, such as fast and undiscerning eating. Our results reveal that the temporal activity of RhoA GTPase alters the Rac1/RhoA balance at the phagocytic cup prior to ingestion, and that this plays a distinct role in orchestrating efferocytosis, with RhoA modulating the rate of engulfment to ensure that the phagocyte engulfs an appropriate amount of the correct material.
Highlights
Efferocytosis, which is the process through which the body clears unwanted or damaged cells, is essential for development, homeostasis, and injury responses
Our results suggest that dynamic Rac1/RhoA balance in the phagocytic cup modulate the critical moment at which a phagocyte decides whether to proceed with eating a meal
Apoptotic cells are efficiently recognized by professional phagocytes, macrophages, and swiftly cleared without cause of inflammation
Summary
Efferocytosis, which is the process through which the body clears unwanted or damaged cells, is essential for development, homeostasis, and injury responses. To examine real-time GTPase activities triggered by physiological targets, L/Stab-2 cells expressing Rac1 or RhoA biosensors were combined with excess number of mouse thymocytes in which apoptosis had been induced by dexamethasone treatment. The spatiotemporal activities of Rac1 and RhoA at the phagocytic cup during the engulfment of individual apoptotic cells
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