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PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance

Nature Medicine volume 15, pages 1266–1272 (2009)Cite this article

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-δ (PPAR-δ) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-δ 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-δ has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.

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Figure 1: PPAR-δ orchestrates timely disposal of apoptotic cells.
Figure 2: PPAR-δ regulates expression of opsonins in macrophages.
Figure 3: PPAR-δ regulates phagocytosis of apoptotic cells via secretion of opsonins.
Figure 4: PPAR-δ is a transcriptional sensor of apoptotic cells in macrophages.
Figure 5: Mice lacking PPAR-δ spontaneously develop autoimmune disease.
Figure 6: Impaired clearance of apoptotic cells and increased autoimmunity in Mac-Ppard−/− mice.

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Acknowledgements

We thank members of the Chawla lab for valuable comment and C.H. Lee and A. Loh for critique on the manuscript. This work was supported by grants made available to A.C. (US National Institutes of Health (DK062386, HL076746 and DK081405) and Rita Allen Foundation), to L.S. (US National Multiple Sclerosis Society) and to S.A.M. (US National Institutes of Health (DK67592 and DE14385)). Support was provided by Stanford Medical Scientist Training Program (J.I.O. and A.R.E.), American Heart Association (J.I.O.), Dean's Fellowship (J.E.H.), Howard Hughes Medical Institute Gilliam fellowship (A.R.E.) and US National Institutes of Health AI066402 (R.R.R.-G.).

Author information

Author notes

  1. Lata Mukundan, Justin I Odegaard and Christine R Morel: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Metabolism and Gerontology, Stanford University School of Medicine, Stanford, California, USA

    Lata Mukundan, Justin I Odegaard, Christine R Morel, Jose E Heredia, Julia W Mwangi, Roberto R Ricardo-Gonzalez, Y P Sharon Goh, Alex Red Eagle, Jennifer U H Awakuni, Khoa D Nguyen & Ajay Chawla

  2. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

    Justin I Odegaard & Sara A Michie

  3. Graduate Program in Biomedical Sciences, Baylor Institute for Immunology Research, Baylor University, Dallas, Texas, USA

    Christine R Morel

  4. Graduate Program in Immunology, Stanford University School of Medicine, Stanford, California, USA

    Roberto R Ricardo-Gonzalez, Y P Sharon Goh, Khoa D Nguyen & Ajay Chawla

  5. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Alex Red Eagle

  6. Department of Neurology and Neurological Studies, Stanford University School of Medicine, Stanford, California, USA

    Shannon E Dunn & Lawrence Steinman

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Contributions

L.M, J.I.O. and C.R.M. were involved in project planning, experimental work and data analysis; J.E.H., R.R.R.-G., J.W.M., A.R.E., S.E.D, J.U.H.A., Y.P.S.G. and K.D.N. performed experimental work; S.A.M. and L.S. were involved in project planning; and A.C. was involved in project planning, data analysis and manuscript preparation.

Corresponding author

Correspondence to Ajay Chawla.

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Mukundan, L., Odegaard, J., Morel, C. et al. PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15, 1266–1272 (2009). https://doi.org/10.1038/nm.2048

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