The Journal of Experimental Medicine
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Published online 9 August 2004 doi:10.1084/jem.20040342
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 4, 459-467
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Masking of Phosphatidylserine Inhibits Apoptotic Cell Engulfment and Induces Autoantibody Production in Mice

Kenichi Asano1,3, Miyu Miwa3, Keiko Miwa4, Rikinari Hanayama1, Hiroko Nagase1, Shigekazu Nagata1,2,4, and Masato Tanaka1,3

1 Department of Genetics, Osaka University Medical School, and 2 Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
3 Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan
4 Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan

Address correspondence to Masato Tanaka, Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. Phone: 81-45-503-9686; Fax: 81-45-503-9685; email: mtanaka{at}rcai.riken.jp

Apoptotic cells are rapidly phagocytosed by professional phagocytes, such as macrophages and dendritic cells. This process prevents the release of potentially noxious or immunogenic intracellular materials from dying cells, and is thought to play a critical role for the maintenance of normal functions in surrounding tissues. Milk fat globule-EGF-factor 8 (MFG-E8), secreted by activated macrophages and immature dendritic cells, links apoptotic cells and phagocytes, and promotes phagocytosis of apoptotic cells. Here, we report that an MFG-E8 mutant, designated as D89E, carrying a point mutation in an RGD motif, inhibited not only the phagocytosis of apoptotic cells by a wide variety of phagocytes, but also inhibited the enhanced production of IL-10 by thioglycollate-elicited peritoneal macrophages phagocytosing apoptotic cells. When intravenously injected into mice, the D89E protein induced the production of autoantibodies including antiphospholipids antibodies and antinuclear antibodies. The production of autoantibodies was enhanced by the coinjection of syngeneic apoptotic thymocytes. After the induction of autoantibody production by D89E, the treated mice showed a long-term elevation of the titer for autoantibodies, and developed IgG deposition in the glomeruli. These results indicated that the impairment of apoptotic cell phagocytosis led to autoantibody production.

Key Words: apoptosis • phagocytosis • MFG-E8 • phosphatidylserine • autoimmunity

Abbreviations used in this paper: ANA, antinuclear antibody; BMDM, bone marrow–derived macrophage; CL, cardiolipin; ds, double stranded; MFG-E8, milk fat globule-EGF-factor 8; PS, phosphatidylserine.


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