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Published online before print January 2, 2004

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(Journal of Leukocyte Biology. 2004;75:705-713.)
© 2004 by Society for Leukocyte Biology

The receptor tyrosine kinase MerTK activates phospholipase C 2 during recognition of apoptotic thymocytes by murine macrophages

Jill C. Todt^*, Bin Hu^* and Jeffrey L. Curtis^*,,,,1

^* Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine,
Comprehensive Cancer Center, and
Graduate Program in Immunology, University of Michigan Health Care System, Ann Arbor; and
Pulmonary & Critical Care Medicine Section, Medical Service, Department of Veterans Affairs Health Care System, Ann Arbor, Michigan

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

Apoptotic leukocytes must be cleared efficiently by macrophages (Mø). Apoptotic cell phagocytosis by Mø requires the receptor tyrosine kinase (RTK) MerTK (also known as c-Mer and Tyro12), the phosphatidylserine receptor (PS-R), and the classical protein kinase C (PKC) isoform ßII, which translocates to Mø membrane and cytoskeletal fractions in a PS-R-dependent manner. How these molecules cooperate to induce phagocytosis is unknown. As the phosphatidylinositol-specific phospholipase (PI–PLC) 2 is downstream of RTKs in some cell types and can activate classical PKCs, we hypothesized that MerTK signals via PLC 2. To test this hypothesis, we examined the interaction of MerTK and PLC 2 in resident, murine peritoneal (P)Mø and in the murine Mø cell line J774A.1 (J774) following exposure to apoptotic thymocytes. We found that as with PMø, J774 phagocytosis of apoptotic thymocytes was inhibited by antibody against MerTK. Western blotting and immunoprecipitation showed that exposure to apoptotic cells produced three time-dependent changes in PMø and J774: tyrosine phosphorylation of MerTK; association of PLC 2 with MerTK; and tyrosine phosphorylation of PLC 2. Cross-linking MerTK using antibody also induced phosphorylation of PLC 2 and its association with MerTK. A PI–PLC appears to be required for phagocytosis of apoptotic cells, as the PI–PLC inhibitor Et-18-OCH3 and the PLC inhibitor U73122, but not the inactive control U73343, blocked phagocytosis without impairing adhesion. On apoptotic cell adhesion to Mø, MerTK signals at least in part via PLC 2.

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

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