PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance
Open accessAbstract
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-delta (PPAR-delta) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-delta 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-delta 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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Modulating microglial activation status by targeting nuclear receptors appears to restore the competence of these cells to phagocytose and clear amyloid in the AD brain.
“Thus, modulating microglial activation status by targeting nuclear receptors appears to restore the competence of these cells to phagocytose and clear amyloid in the AD brain (Mukundan et al., 2009; Chinetti-Gbaguidi et al., 2011).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Mukundan et al., 2009
The Results section ('PPAR-δ regulates opsonin gene expression in macrophages'; page unavailable) reports that activating the nuclear receptor PPAR-δ increased macrophage uptake of apoptotic cells. The paper does not establish that targeting nuclear receptors restores microglial clearance of amyloid in an Alzheimer’s disease brain; its experiments concern macrophages and apoptotic cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredActivation of nuclear receptors suppresses NFκB-mediated inflammatory responses and activates phagocytic machinery.
“Activation of these nuclear receptors suppresses NFκB-mediated inflammatory responses and activates their phagocytic machinery (Zelcer et al., 2007; Mukundan et al., 2009; Glass and Saijo, 2010).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Mukundan et al., 2009
The Results section reports that PPAR-δ activation increases opsonin expression and apoptotic-cell uptake, and that PPAR-δ is required for the observed suppression of pro-inflammatory cytokines after apoptotic-cell feeding. The cited paper does not establish that this suppression is NFκB-mediated. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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- Authors
- Mukundan, L., Odegaard, J. I., Morel, C. R., Heredia, J. E., Mwangi, J. W., Ricardo-Gonzalez, R. R., Goh, Y. P. S., Eagle, A. R., Dunn, S. E., Awakuni, J. U. H., Nguyen, K. D., Steinman, L., Michie, S. A., & Chawla, A.
- Affiliations
- Stanford Medicine (US)
- Baylor University (US)
- Corresponding author
- Chawla, Ajay
- Venue
- Nature Medicine
- Published
- 2009-10-18
- Volume
- 15
- Issue
- 11
- Pages
- 1266-1272
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2783696
- OpenAlex
- W2116505573
- Cited by
- 368
- References
- 45
- Citations by year
- 2026: 9 · 2025: 23 · 2024: 14 · 2023: 19 · 2022: 22 · 2021: 23 · 2020: 23 · 2019: 18 · 2018: 14 · 2017: 33 · 2016: 15 · 2015: 18 · 2014: 23 · 2013: 31 · 2012: 27
- FWCI
- 11.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (HL076746, R01HL076746)
- National Institute of Allergy and Infectious Diseases (F31AI066402, AI066402, T32AI007290)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK67592, DK081405, R01DK081405, DK062386, R01DK067592, K08DK062386, R01DK076760)
- National Institute of Dental and Craniofacial Research (R01DE014385, DE14385)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- PPARδ, efferocytosis, macrophages, opsonins, C1q, autoimmunity, systemic lupus erythematosus, autoimmune kidney disease, autoantibodies, anti-inflammatory cytokines, self-tolerance, fatty acid sensing, transcriptional regulation
- MeSH terms
- Animals, Autoantibodies, Autoimmune Diseases, Cells, Cultured, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Fluoresceins, Gene Expression Regulation, Humans, Immune Tolerance, Macrophages, Mice, Inbred BALB C, Opsonin Proteins, Phagocytosis, Phenols, Promoter Regions, Genetic, RNA, Messenger, Sulfhydryl Compounds, Thiazoles, Thymus Gland, Time Factors, Autoimmunity, Cytokines, Apoptosis, Mice, Knockout, Hyaluronan Receptors, Mitochondrial Proteins, CD11b Antigen, PPAR delta, Mice
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