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, Ping Wang

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Sepsis, a highly lethal systemic inflammatory syndrome, is associated with increases of proinflammatory cytokines (e.g., TNF-α, 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.

Original languageEnglish (US)
Pages (from-to)5983-5990
Number of pages8
JournalJournal of Immunology
Volume183
Issue number9
DOIs
StatePublished - Nov 1 2009
Externally publishedYes

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Exosomes
Epidermal Growth Factor
Dendritic Cells
Sepsis
Cytophagocytosis
HMGB1 Protein
Cytokines
Mortality
Factor VIII
Nuclear Proteins
Punctures
Phagocytosis
Ligation
Theoretical Models
Necrosis
Spleen
milk fat globule
Apoptosis
Inflammation
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor VIII. / Miksa, Michael; Wu, Rongqian; Dong, Weifeng; Komura, Hidefumi; Amin, Dhruv; Ji, Youxin; Wang, Zhimin; Wang, Haichao; Ravikumar, Thanjavur S.; Tracey, Kevin J.; Wang, Ping.

In: Journal of Immunology, Vol. 183, No. 9, 01.11.2009, p. 5983-5990.

Research output: Contribution to journalArticle

Miksa, M, Wu, R, Dong, W, Komura, H, Amin, D, Ji, Y, Wang, Z, Wang, H, Ravikumar, TS, Tracey, KJ & Wang, P 2009, 'Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor VIII', Journal of Immunology, vol. 183, no. 9, pp. 5983-5990. https://doi.org/10.4049/jimmunol.0802994
Miksa, Michael ; Wu, Rongqian ; Dong, Weifeng ; Komura, Hidefumi ; Amin, Dhruv ; Ji, Youxin ; Wang, Zhimin ; Wang, Haichao ; Ravikumar, Thanjavur S. ; Tracey, Kevin J. ; Wang, Ping. / Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor VIII. In: Journal of Immunology. 2009 ; Vol. 183, No. 9. pp. 5983-5990.
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