The receptor tyrosine kinase MerTK activates phospholipase C γ2 during recognition of apoptotic thymocytes by murine macrophages

Journal of Leukocyte Biology

Jeffrey L. Curtis¹  Jill C. Todt²  Bin Hu² 

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

关键词: apoptosis;    phagocytosis;    signal transduction;    protein kinases/phosphatases;    mice;    inbred strains;   

DOI  :  10.1189/jlb.0903439

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 βII, 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) γ2 is downstream of RTKs in some cell types and can activate classical PKCs, we hypothesized that MerTK signals via PLC γ2. To test this hypothesis, we examined the interaction of MerTK and PLC γ2 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 γ2 with MerTK; and tyrosine phosphorylation of PLC γ2. Cross-linking MerTK using antibody also induced phosphorylation of PLC γ2 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 γ2.

【 授权许可】

Unknown