title: 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance.
abstract: 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 Ly6C(hi) 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.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Olga V
authors.initials: OV
authors.lastname: Oskolkova
authors.forename: Susanne
authors.initials: S
authors.lastname: Aschermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bicker
authors.forename: Natacha
authors.initials: N
authors.lastname: Ipseiz
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sarter
authors.forename: Benjamin
authors.initials: B
authors.lastname: Frey
authors.forename: Tobias
authors.initials: T
authors.lastname: Rothe
authors.forename: Reinhard
authors.initials: R
authors.lastname: Voll
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Valery N
authors.initials: VN
authors.lastname: Bochkov
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001092:Arachidonate 12-Lipoxygenase / Q000276:immunology* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000276:immunology; D008055:Lipids / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D017634:Self Tolerance / Q000276:immunology*
chemical_list: C475064:12-15-lipoxygenase; D008055:Lipids; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase