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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 ORCID:, 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: 26 Oct 2022 08:28

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