Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.0307135 on May 29, 2008

Published online before print May 29, 2008
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(Journal of Leukocyte Biology. 2008;84:510-518.)
© 2008 by Society for Leukocyte Biology

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

Jill C. Todt*, Bin Hu* and Jeffrey L. Curtis*,{dagger},{ddagger},§,1

* Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine,
{dagger} Comprehensive Cancer Center, and
{ddagger} Graduate Program in Immunology, University of Michigan Health Care System, and
§ Pulmonary and Critical Care Medicine Section, Medical Service, Department of Veterans Affairs Care System, Ann Arbor, Michigan, USA

1 Correspondence: Pulmonary and Critical Care Medicine Section (506/111G), 2215 Fuller Road, Ann Arbor, MI 48105-2303, USA. E-mail: jlcurtis{at}umich.edu

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 C{gamma}2, 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.

Key Words: apoptosis • phagocytosis • signal transduction • protein kinases/phosphatases • mice • inbred strains






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