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Immature Dendritic Cell-Derived Exosomes Rescue Septic Animals Via Milk Fat Globule Epidermal Growth Factor VIII

Michael Miksa,^* Rongqian Wu,^* Weifeng Dong, Hidefumi Komura, Dhruv Amin, Youxin Ji, Zhimin Wang, Haichao Wang,^* Thanjavur S. Ravikumar, Kevin J. Tracey,^* and Ping Wang^2*

^*The Feinstein Institute for Medical Research, and Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY 11030

Sepsis, a highly lethal systemic inflammatory syndrome, is associated with increases of proinflammatory cytokines (e.g., TNF-, HMGB1) and the accumulation of apoptotic cells that have the potential to be detrimental. Depending on the timing and tissue, prevention of apoptosis in sepsis is beneficial; however, thwarting the development of secondary necrosis through the active removal of apoptotic cells by phagocytosis may offer a novel anti-sepsis therapy. Immature dendritic cells (IDCs) release exosomes that contain milk fat globule EGF factor VIII (MFGE8), a protein required to opsonize apoptotic cells for phagocytosis. In an experimental sepsis model using cecal ligation and puncture, we found that MFGE8 levels decreased in the spleen and blood, which was associated with impaired apoptotic cell clearance. Administration of IDC-derived exosomes promoted phagocytosis of apoptotic cells and significantly reduced mortality. Treatment with recombinant MFGE8 was equally protective, whereas MFGE8-deficient mice suffered from increased mortality. IDC exosomes also attenuated the release of proinflammatory cytokines in septic rats. Liberation of HMGB1, a nuclear protein that contributes to inflammation upon release from unengulfed apoptotic cells, was prevented by MFGE8-mediated phagocytosis in vitro. We conclude that IDC-derived exosomes attenuate the acute systemic inflammatory response in sepsis by enhancing apoptotic cell clearance via MFGE8.

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 study was supported by Grants R01 GM057468, R01 GM053008, and R01 AG028352 from National Institutes of Health (to P.W.).

² Address correspondence and reprint requests to Dr. Ping Wang, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: pwang{at}nshs.edu

³ Abbreviations used in this paper: DC, dendritic cell; IDC, immature DC; MFGE8, milk fat globule EGF factor VIII; rmMFGE8, recombinant murine MFGE8; CLP, cecal ligation and puncture; HMGB1, high-mobility group box 1; WT, wild type.