Journal
IMMUNITY
Volume 36, Issue 5, Pages 834-846Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2012.03.010
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Funding
- Deutsche Forschungsgemeinschaft [SCHE1583, KR3523, FG 661, SFB643, SPP1468-IMMUNOBONE]
- ELAN of the University of Erlangen-Nuremberg
- MASTERSWITCH of the European Union
- IMI
- Interdisciplinary Centre for Clinical Research
- osterreichische Forschungsforderungsgesellschaft [815445]
- Fonds zur Forderung wissenschaftlicher Forschung [P20801-B11, P22267-B11]
- Austrian Science Fund (FWF) [P 22267] Funding Source: researchfish
- Austrian Science Fund (FWF) [P20801, P22267] Funding Source: Austrian Science Fund (FWF)
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Noninflammatory clearance of apoptotic cells (ACs) is crucial to maintain self-tolerance. Here, we have reported a role for the enzyme 12/15-lipoxygenase (12/15-LO) as a central factor governing the sorting of ACs into differentially activated monocyte subpopulations. During inflammation, uptake of ACs was confined to a population of 12/15-LO-expressing, alternatively activated resident macrophages (resM Phi), which blocked uptake of ACs into freshly recruited inflammatory Ly6C(hi) monocytes in a 12/15-LO-dependent manner. ResM Phi. exposed 12/15-LO-derived oxidation products of phosphatidylethanolamine (oxPE) on their plasma membranes and thereby generated a sink for distinct soluble receptors for ACs such as milk fat globule-EGF factor 8, which were essential for the uptake of ACs into inflammatory monocytes. Loss of 12/15-LO activity, in turn, resulted in an aberrant phagocytosis of ACs by inflammatory monocytes, subsequent antigen presentation of AC-derived antigens, and a lupus-like autoimmune disease. Our data reveal an unexpected key role for enzymatic lipid oxidation during the maintenance of self-tolerance.
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