PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance.
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.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Lata
L
Mukundan
Justin I
JI
Odegaard
Christine R
CR
Morel
Jose E
JE
Heredia
Julia W
JW
Mwangi
Roberto R
RR
Ricardo-Gonzalez
Y P Sharon
YP
Goh
Alex Red
AR
Eagle
Shannon E
SE
Dunn
Jennifer U H
JU
Awakuni
Khoa D
KD
Nguyen
Lawrence
L
Steinman
Sara A
SA
Michie
Ajay
A
Chawla
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015551:Autoimmunity / Q000187:drug effects / Q000502:physiology*; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009895:Opsonin Proteins / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D010636:Phenols; D013438:Sulfhydryl Compounds
D001323:Autoantibodies; D039481:CD11b Antigen; D016207:Cytokines; D005452:Fluoresceins; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D009895:Opsonin Proteins; D047494:PPAR delta; D012333:RNA, Messenger; D013844:Thiazoles; C490193:C1qbp protein, mouse; C069306:5-chloromethylfluorescein; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds