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-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Autoantibodies / immunology
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Autoantibodies / metabolism
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Autoimmune Diseases / genetics
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Autoimmune Diseases / pathology
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Autoimmune Diseases / physiopathology
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Autoimmunity / drug effects
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Autoimmunity / physiology*
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CD11b Antigen / metabolism
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Cells, Cultured
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Cytokines / metabolism
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Disease Models, Animal
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Enzyme-Linked Immunosorbent Assay / methods
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Female
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Fluoresceins
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Humans
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Hyaluronan Receptors / metabolism
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Immune Tolerance / drug effects
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Immune Tolerance / immunology*
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mitochondrial Proteins
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Opsonin Proteins / genetics
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Opsonin Proteins / metabolism
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PPAR delta / agonists
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PPAR delta / deficiency
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PPAR delta / genetics
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PPAR delta / metabolism*
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Phagocytosis / drug effects
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Phagocytosis / immunology
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / physiology
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RNA, Messenger / metabolism
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Thiazoles / pharmacology
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Thymus Gland / cytology
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Time Factors
Substances
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Autoantibodies
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C1qbp protein, mouse
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CD11b Antigen
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Cytokines
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Fluoresceins
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Hyaluronan Receptors
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Mitochondrial Proteins
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Opsonin Proteins
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PPAR delta
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RNA, Messenger
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Thiazoles
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5-chloromethylfluorescein
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(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid