Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Savill, J. & Fadok, V. Corpse clearance defines the meaning of cell death. Nature 407, 784–788 (2000).

    Article  CAS  Google Scholar 

  2. Henson, P.M., Bratton, D.L. & Fadok, V.A. The phosphatidylserine receptor: a crucial molecular switch? Nat. Rev. Mol. Cell Biol. 2, 627–633 (2001).

    Article  CAS  Google Scholar 

  3. Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975 (2002).

    Article  CAS  Google Scholar 

  4. Lauber, K., Blumenthal, S.G., Waibel, M. & Wesselborg, S. Clearance of apoptotic cells: getting rid of the corpses. Mol. Cell 14, 277–287 (2004).

    Article  CAS  Google Scholar 

  5. Erwig, L.P. & Henson, P.M. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 15, 243–250 (2008).

    Article  CAS  Google Scholar 

  6. Ravichandran, K.S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nat. Rev. Immunol. 7, 964–974 (2007).

    Article  CAS  Google Scholar 

  7. Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007).

    Article  CAS  Google Scholar 

  8. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).

    Article  CAS  Google Scholar 

  9. Scott, R.S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001).

    Article  CAS  Google Scholar 

  10. Cohen, P.L. et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135–140 (2002).

    Article  CAS  Google Scholar 

  11. Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).

    Article  CAS  Google Scholar 

  12. Chawla, A., Repa, J.J., Evans, R.M. & Mangelsdorf, D.J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).

    Article  CAS  Google Scholar 

  13. Evans, R.M., Barish, G.D. & Wang, Y.-X. PPARs and the complex journey to obesity. Nat. Med. 10, 355–361 (2004).

    Article  CAS  Google Scholar 

  14. Odegaard, J.I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

    Article  CAS  Google Scholar 

  15. Odegaard, J.I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).

    Article  CAS  Google Scholar 

  16. Kang, K. et al. Adipocyte-derived TH2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485–495 (2008).

    Article  CAS  Google Scholar 

  17. Blander, J.M. & Medzhitov, R. Regulation of phagosome maturation by signals from Toll-like receptors. Science 304, 1014–1018 (2004).

    Article  CAS  Google Scholar 

  18. Hess, K.L., Babcock, G.F., Askew, D.S. & Cook-Mills, J.M. A novel flow cytometric method for quantifying phagocytosis of apoptotic cells. Cytometry 27, 145–152 (1997).

    Article  CAS  Google Scholar 

  19. Desvergne, B., Michalik, L. & Wahli, W. Transcriptional regulation of metabolism. Physiol. Rev. 86, 465–514 (2006).

    Article  CAS  Google Scholar 

  20. Barish, G.D., Narkar, V.A. & Evans, R.M. PPARδ: a dagger in the heart of the metabolic syndrome. J. Clin. Invest. 116, 590–597 (2006).

    Article  CAS  Google Scholar 

  21. Sznaidman, M.L. et al. Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity. Bioorg. Med. Chem. Lett. 13, 1517–1521 (2003).

    Article  CAS  Google Scholar 

  22. Slingsby, J.H. et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum. 39, 663–670 (1996).

    Article  CAS  Google Scholar 

  23. Armbrust, T., Nordmann, B., Kreissig, M. & Ramadori, G. C1Q synthesis by tissue mononuclear phagocytes from normal and from damaged rat liver: up-regulation by dexamethasone, down-regulation by interferon γ and lipopolysaccharide. Hepatology 26, 98–106 (1997).

    CAS  PubMed  Google Scholar 

  24. Breitkopf, K. et al. Thrombospondin 1 acts as a strong promoter of transforming growth factor β effects via two distinct mechanisms in hepatic stellate cells. Gut 54, 673–681 (2005).

    Article  CAS  Google Scholar 

  25. Petry, F., Botto, M., Holtappels, R., Walport, M.J. & Loos, M. Reconstitution of the complement function in C1q-deficient (C1qa−/−) mice with wild-type bone marrow cells. J. Immunol. 167, 4033–4037 (2001).

    Article  CAS  Google Scholar 

  26. Voll, R.E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    Article  CAS  Google Scholar 

  27. Fadok, V.A., Bratton, D.L. & Henson, P.M. Phagocyte receptors for apoptotic cells: recognition, uptake and consequences. J. Clin. Invest. 108, 957–962 (2001).

    Article  CAS  Google Scholar 

  28. Taylor, P.R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000).

    Article  CAS  Google Scholar 

  29. Satoh, M. & Reeves, W.H. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J. Exp. Med. 180, 2341–2346 (1994).

    Article  CAS  Google Scholar 

  30. Satoh, M., Kumar, A., Kanwar, Y.S. & Reeves, W.H. Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane. Proc. Natl. Acad. Sci. USA 92, 10934–10938 (1995).

    Article  CAS  Google Scholar 

  31. Hicks, J. & Bullard, D.C. Review of autoimmune (lupus-like) glomerulonephritis in murine models. Ultrastruct. Pathol. 30, 345–359 (2006).

    Article  Google Scholar 

  32. Napirei, M. et al. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25, 177–181 (2000).

    Article  CAS  Google Scholar 

  33. Gunnia, U.B., Amenta, P.S., Seibold, J.R. & Thomas, T.J. Successful treatment of lupus nephritis in MRL-lpr/lpr mice by inhibiting ornithine decarboxylase. Kidney Int. 39, 882–890 (1991).

    Article  CAS  Google Scholar 

  34. Kelley, V.E. & Roths, J.B. Interaction of mutant lpr gene with background strain influences renal disease. Clin. Immunol. Immunopathol. 37, 220–229 (1985).

    Article  CAS  Google Scholar 

  35. Morel, L., Yu, Y., Blenman, K.R., Caldwell, R.A. & Wakeland, E.K. Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain. Mamm. Genome 7, 335–339 (1996).

    Article  CAS  Google Scholar 

  36. Mevorach, D., Zhou, J.L., Song, X. & Elkon, K.B. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J. Exp. Med. 188, 387–392 (1998).

    Article  CAS  Google Scholar 

  37. Wermeling, F. et al. Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus. J. Exp. Med. 204, 2259–2265 (2007).

    Article  CAS  Google Scholar 

  38. Graham, R.R., Hom, G., Ortmann, W. & Behrens, T.W. Review of recent genome-wide association scans in lupus. J. Intern. Med. 265, 680–688 (2009).

    Article  CAS  Google Scholar 

  39. Harley, J.B., Kelly, J.A. & Kaufman, K.M. Unraveling the genetics of systemic lupus erythematosus. Springer Semin. Immunopathol. 28, 119–130 (2006).

    Article  CAS  Google Scholar 

  40. Surh, C.D. & Sprent, J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100–103 (1994).

    Article  CAS  Google Scholar 

  41. Fadok, V.A. Clearance: the last and often forgotten stage of apoptosis. J. Mammary Gland Biol. Neoplasia 4, 203–211 (1999).

    Article  CAS  Google Scholar 

  42. Castrillo, A. & Tontonoz, P. Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Annu. Rev. Cell Dev. Biol. 20, 455–480 (2004).

    Article  CAS  Google Scholar 

  43. A.-Gonzales, N. et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245–258 (2009).

    Article  Google Scholar 

  44. Barak, Y. et al. Effects of peroxisome proliferator–activated receptor δ on placentation, adiposity and colorectal cancer. Proc. Natl. Acad. Sci. USA 99, 303–308 (2002).

    Article  CAS  Google Scholar 

  45. Chang, M.K. et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J. Exp. Med. 200, 1359–1370 (2004).

    Article  CAS  Google Scholar 

Download references

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

Authors
  1. Lata Mukundan
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Justin I Odegaard
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Christine R Morel
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Jose E Heredia
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Julia W Mwangi
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Roberto R Ricardo-Gonzalez
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Y P Sharon Goh
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Alex Red Eagle
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Shannon E Dunn
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Jennifer U H Awakuni
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Khoa D Nguyen
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Lawrence Steinman
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Sara A Michie
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Ajay Chawla
    View author publications

    You can also search for this author inPubMed Google Scholar

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Methods (PDF 1743 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2048

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing