Daria Martin, Schering Stiftung Projektraum

 

Avrion Mitchison Prize 2012

Dr. med. Stefan Uderhardt

University of Erlangen-Nuremberg, Rheumatology and Immunology

"12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance"

Dr. Stefan Uderhardt is the recipient of the 2012 Avrion Mitchison Prize for Rheumatology for his work, “12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance.”

Uderhardt, born in 1984, studied medicine at the University of Erlangen-Nuremberg from 2004 until 2010. From 2008 until 2011, he worked on his dissertation in the lab of Dr. Gerhard Krönke at the Institute for Rheumatology and Clinical Immunology at the University’s Medical Clinic 3, writing his thesis on the “Molecular Regulation of Bone Remodeling in Inflammatory Arthritis.” Since 2010, he has been a resident physician and research associate at the Medical Clinic 3.

At the award ceremony, Dr. Stefan Uderhardt will present his current research, “12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance”.

“One major task of the immune system is to efficiently eliminate invading pathogens and to maintain immunological self-tolerance at the same time. However, during inflammation and consequent tissue damage, the innate immune system is challenged with both pathogens and dying cells. Defective clearance of apoptotic cells has emerged as a crucial factor in the development of autoimmune diseases. The ingestion and processing of self-antigens derived from apoptotic cells by inflammatory antigen-presenting cells could provoke an unwanted immune response and could result in a break of self-tolerance leading to autoimmunity. Therefore, there must be mechanisms, especially under inflammatory conditions, which regulate a selective cellular sorting of different antigens into differentially-activated phagocyte compartments.

We have identified the lipid-oxidizing enzyme 12/15-lipoxygenase (12/15-LO) as a crucial factor orchestrating the non-inflammatory clearance of apoptotic cells under inflammatory conditions. During inflammation, the uptake of apoptotic cells was strictly confined to a population of alternatively-activated, 12/15-LO-expressing, resident tissue macrophages. Pathogens like bacteria, on the other hand, were mainly taken up into freshly recruited inflammatory phagocytes. Here, resident macrophages could actively block the uptake of apoptotic cells into inflammatory macrophages in a 12/15-LO-dependend manner. By exposing 12/15-LO-generated oxidation-products of phosphatidylethanolamin (PE) on the surface of their cell membranes, resident macrophages could eliminate distinct soluble receptors for apoptotic cells such as the milk fat globule-EGF factor 8 (MFGE8), which was utilized by inflammatory phagocytes to take up apoptotic cells. Mass-spectrometry data revealed that specific PE oxidation products were absent in resident macrophages from 12/15-LO knockout mice. 12/15-LO-deficiency, in turn, caused an aberrant uptake of apoptotic cells with a clear shift towards inflammatory macrophages and subsequent presentation of AC-derived self-antigen in vitro and in vivo, respectively. Indeed, we could observe a break of self-tolerance and a lupus-like autoimmune disease in aged 12/15-LO-deficient mice. These mice showed a spontaneous production of autoantibodies and development of glomerulonephritis, both hallmarks of autoimmune diseases like human Systemic Lupus Erythematosus. This phenotype even 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 uncovered a mechanism by which the selective uptake of antigens of different origins into differentially activated phagocyte subsets is orchestrated in a cell- and context-specific manner.”

Award Ceremony on December 4, 2012, at 5:00 p.m.

The Avrion Mitchison Prize, which is funded by the Ernst Schering Foundation, is presented in conjunction with the Albrecht Hasinger Lecture at the German Rheumatism Research Center (DRFZ).

Foyer of the German Rheumatism Research Center Berlin
Charité Mitte Campus
Charitéplatz 1
10117 Berlin
www.drfz.de

2012_Uderhardt_grau

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