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* Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599;
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721;
Molecular Neurobiology Laboratory, The Salk Institute for Biological Sciences, La Jolla, CA 92037; and
Lineberger Comprehensive Cancer Center,
¶ Neuroscience Center, and
|| Program for Molecular Biology and Biotechnology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599
The clearance of apoptotic cells is important for regulating tissue homeostasis, inflammation, and autoimmune responses. The absence of receptor tyrosine kinases (Axl, Mertk, and Tyro3) results in widespread accumulation of apoptotic cells and autoantibody production in mice. In this report, we examine the function of the three family members in apoptotic cell clearance by different phagocytic cell types. Mertk elimination nearly abolished macrophage apoptotic cell phagocytosis; elimination of Axl, Tyro3, or both, reduced macrophage phagocytosis by approximately half, indicating that these also play a role. In contrast, apoptotic cell clearance in splenic and bone marrow-derived dendritic cells (DCs) is prolonged compared with macrophages and relied primarily on Axl and Tyro3. The slower ingestion may be due to lower DC expression of Axl and Tyro3 or absence of GAS6 expression, a known ligand for this receptor family. In vivo, phagocytosis of apoptotic material by retinal epithelial cells required Mertk. Unlike macrophages, there did not appear to be any role for Axl or Tyro3 in retinal homeostasis. Likewise, clearance of apoptotic thymocytes in vivo was dramatically reduced in mertkkd mice, but was normal in axl/tyro3–/– mice. Thus, cell and organ type specificity is clearly delineated, with DCs relying on Axl and Tyro3, retina and thymus requiring Mertk, and macrophages exhibiting an interaction that involves all three family members. Surprisingly, in macrophages, tyrosine phosphorylation of Mertk in response to apoptotic cells is markedly diminished from axl/tyro3–/– mice, suggesting that the interactions of these receptors by heterodimerization may be important in some cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institute for Allergy and Infectious Disease Grant 5-31702.
2 Address correspondence and reprint requests to Dr. Glenn K. Matsushima, Neuroscience Center, 105 Mason Farm Road, Chapel Hill, NC 27599. E-mail address: gkmats{at}med.unc.edu
3 Abbreviations used in this paper: MFG, milk-fat globule; DC, dendritic cell; BMDC, bone marrow-derived DC; IP, immunoprecipitation; MFI, mean fluorescence intensity; PRL, photoreceptor layer; ONL, outer nuclear layer; sAxl, soluble form of Axl. GAS6, growth arrest specific gene.
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