The scavenger receptor SR-A I/II (CD204) signals via the receptor tyrosine kinase Mertk during apoptotic cell uptake by murine macrophages

Abstract

Apoptotic cells (AC) must be cleared by macrophages (Mø) to resolve inflammation effectively. Mertk and scavenger receptor A (SR-A) are two of many receptors involved in AC clearance. As SR-A lacks enzymatic activity or evident intracellular signaling motifs, yet seems to signal in some cell types, we hypothesized that SR-A signals via Mer receptor tyrosine kinase (Mertk), which contains a multisubstrate docking site. We induced apoptosis in murine thymocytes by dexamethasone and used Western blotting and immunoprecipitation to analyze the interaction of Mertk and SR-A in the J774A.1 (J774) murine Mø cell line and in peritoneal Mø of wild-type mice and SR-A-/- mice. Phagocytosis (but not adhesion) of AC by J774 was inhibited by anti-SR-A or function-blocking SR-A ligands. In resting J774, SR-A was associated minimally with unphosphorylated (monomeric) Mertk; exposure to AC induced a time-dependent increase in association of SR-A with Mertk in a direct or indirect manner. Anti-SR-A inhibited AC-induced phosphorylation of Mertk and of phospholipase Cgamma2, essential steps in AC ingestion. Relative to tissue Mø of wild-type mice, AC-induced Mertk phosphorylation was reduced and delayed in tissue Mø of SR-A-/- mice, as was in vitro AC ingestion at early time-points. Thus, during AC uptake by murine Mø, SR-A is essential for optimal phosphorylation of Mertk and subsequent signaling required for AC ingestion. These data support the Mertk/SR-A complex as a potential target to manipulate AC clearance and hence, resolution of inflammation and infections.

Hemophagocytic Macrophages in Murine Typhoid Fever Have an Anti-Inflammatory Phenotype

“…However, not all M2 markers are highly expressed on hemophagocytic macrophages in mice, likely reflecting the multiple different classes of M2 macrophages that have been described (20,22). For instance, macrophages that engulf apoptotic cells are considered to have an M2 activation state and can express SRA/ CD204 (36). Hemophagocytic macrophages express lower levels of SRA/CD204 than 2-4N macrophages, suggesting that 6Nϩ macrophages represent a different kind of M2 macrophage that does not remove apoptotic cells.…”

Biology of the TAM Receptors

“…1) (Wu et al 2006;Nagata et al 2010). At the same time, this ligand must also activate the tyrosine kinase activity of the TAM receptor for the process of phagocytosis to go forward (Scott et al 2001;Mahajan and Earp 2003;Tibrewal et al 2008;Todt et al 2008;Lemke and Burstyn-Cohen 2010).…”

TNF-α, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages

“…Further studies investigated the role of GAS6 receptors in the control of DC activation. They demonstrate that Mer is involved in apoptotic cell uptake [14] and is involved in the inhibition of proinflammatory cytokine production by DC inducing PI3K/ Akt activation and NF-B nuclear translocation inhibition [15].…”