Volume 9 Supplement 2
12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance
© Uderhardt et al; licensee BioMed Central Ltd. 2011
Published: 23 November 2011
The coordinated and non-inflammatory phagocytosis of apoptotic cells is crucial to maintain immunological tolerance. During inflammation, however, ingestion of apoptotic material by inflammatory phagocytes can provoke a break in self-tolerance. Hence, and though poorly understood, mechanisms governing the sorting of apoptotic cells into distinct and differentially-activated subsets of phagocytes are essential to prevent autoimmunity.
Here we identify the enzyme 12/15-lipoxygenase (12/15-LO) as a crucial factor orchestrating the clearance of apoptotic cells under inflammatory conditions. During peritonitis, the ingestion of apoptotic cells is confined to a distinct population of alternatively-activated, 12/15-LO-expressing resident macrophages (resMΦ). Deletion of 12/15-LO changed this pattern and neighbouring inflammatory macrophages (infMΦ) start to engulf apoptotic cells.
We hypothesized that resMΦ exert a paracrine and 12/15-LO-mediated inhibitory activity on the phagocytic capacity of infMΦ and identified oxidation products of phosphatidyl ethanolamine (oxPE) as the corresponding mediators. oxPE is generated by the action of 12/15-LO in resMΦ and consequently exposed on the macrophages' surfaces. Here, oxPE binds, blocks and scavenges soluble MFG-E8 protein and thereby selectively blocks the major pathway involved in the uptake of apoptotic cells into infMΦ. In turn, we observed a break in self-tolerance and lupus-like autoimmune disease in aged 12/15-LO-deficient mice. These mice displayed spontaneous production of autoantibodies and glomerulonephritis, which both exacerbated after apoptotic challenge in the pristane-induced model of experimental murine lupus.
Our data point towards a so far unrecognized role for enzymatic lipid oxidation during the maintenance of self-tolerance and identify a mechanism, which orchestrates the cell- and context-specific uptake of antigens by different subsets of phagocytes, imposing a new paradigm in our understanding of the clearance of apoptotic cells.
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.