Article abstract
Nature Medicine 15, 1266 - 1272 (2009)
Published online: 18 October 2009 | doi:10.1038/nm.2048
PPAR-
senses and orchestrates clearance of apoptotic cells to promote tolerance
Lata Mukundan1,7, Justin I Odegaard1,2,7, Christine R Morel1,3,7, Jose E Heredia1, Julia W Mwangi1, Roberto R Ricardo-Gonzalez1,4, Y P Sharon Goh1,4, Alex Red Eagle1,5, Shannon E Dunn6, Jennifer U H Awakuni1, Khoa D Nguyen1,4, Lawrence Steinman6, Sara A Michie2 & Ajay Chawla1,4
Abstract
Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator–activated receptor-
(PPAR-) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR- decreases expression of opsonins such as complement component-1qb (C1qb), resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific Ppard-/- mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR- has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.
- Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
- Graduate Program in Biomedical Sciences, Baylor Institute for Immunology Research, Baylor University, Dallas, Texas, USA.
- Graduate Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
- Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
- Department of Neurology and Neurological Studies, Stanford University School of Medicine, Stanford, California, USA.
- These authors contributed equally to this work.
Correspondence to: Ajay Chawla1,4 e-mail: achawla@stanford.edu
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