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

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• 作者：Stefan Uderhardt¹ ; ² ; Martin Herrmann¹ ; Olga  ; V. Oskolkova⁴ ; Susanne Aschermann⁵ ; Wolfgang Bicker⁶ ; Natacha Ipseiz¹ ; ² ; Kerstin Sarter¹ ; Benjamin Frey³ ; Tobias Rothe¹ ; ² ; Reinhard Voll¹ ; Falk Nimmerjahn⁵ ; Valery  ; N. Bochkov⁴ ; Georg Schett¹ ; Gerhard Krö ; nke¹ ; ² ; ^{gerhard.kroenke@uk-erlangen.de}
• 刊名：Immunity
• 出版年：2012
• 期刊代码：40_10747613
• 类别：imm
• 出版时间：25 May, 2012
• 卷：36
• 期：5
• 页码：834-846
• 文件大小：1942 K

摘要

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Summary

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桅), which blocked uptake of ACs into freshly recruited inflammatory Ly6C^hi monocytes in a 12/15-LO-dependent manner. ResM桅 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.