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12/15-Lipoxygenase Orchestrates the Clearance of Apoptotic Cells and Maintains Immunologic Tolerance

Uderhardt, Stefan, Herrmann, Martin, Oskolkova, Olga V., Aschermann, Susanne, Bicker, Wolfgang, Ipseiz, Natacha, Sarter, Kerstin, Frey, Benjamin, Rothe, Tobias, Voll, Reinhard, Nimmerjahn, Falk, Bochkov, Valery N., Schett, Georg and Krönke, Gerhard 2012. 12/15-Lipoxygenase Orchestrates the Clearance of Apoptotic Cells and Maintains Immunologic Tolerance. Immunity 36 (5) , pp. 834-846. 10.1016/j.immuni.2012.03.010

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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 (resMΦ), which blocked uptake of ACs into freshly recruited inflammatory Ly6Chi monocytes in a 12/15-LO-dependent manner. ResMΦ 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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Elsevier (Cell Press)
ISSN: 1074-7613
Date of Acceptance: 20 March 2012
Last Modified: 19 Dec 2019 16:00

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