Tethering and tickling: a new role for the phosphatidylserine receptor

Abstract

Several receptors are implicated in apoptotic cell (AC) uptake by phagocytic cells; however, their relative dominance in mammalian systems remains to be established. New studies shed light on the role of the phosphatidyl serine (PS) receptor (PSR). Ligation of PSR by PS on AC surfaces is considered essential for signaling uptake of ACs that are tethered to phagocytes via other receptors.

Figure 1.

Phagocyte apoptotic cell interactions. Several receptors are implicated in the uptake of ACs by phagocytes. These receptors interact with their ligands on the AC either directly or via bridging proteins. The dominance, cooperation, and redundancy amongst these receptors are discussed in the text. BC, bovine conglutinin; LA, lactadherin; TSP, thrombospondin. MBL, SPA, BC, and C1q are defense collagens, which bridge AC to phagocytes via calretculin and CD91. LA and TSP are putative bridging molecules for the αvβ3 and αvβ5 integrins, respectively. The latter are thought to cooperate with CD36 in AC uptake. Gas6, a product of growth arrest–specific gene 6, appears to bridge PS with receptor tyrosine kinases such as Mer.

Figure 2.

The dual role of PSR. PSR engagement tickles the phagocyte to take up tethered apoptotic cells, including bystander cells, by macropinocytosis. Internalization requires reorganization of the actin cytoskeleton through activation of the Rho GTPases Rac1, and Cdc42, and the WASp. In this scenario, PSR also has an immunoregulatory role. Signaling through this receptor leads to secretion of immunosuppressive cytokines such as TGF-β and possibly PGE₂, IL-10, and platelet-activating factor (PAF).