One of the roles of macrophages is to engulf apoptotic cells; failure to do so causes inflammation and may trigger autoimmune responses, such as occurs in lupus erythematosus (see commentary by Elkon). During apoptosis, phospholipids are scrambled between the inner and outer leaflets of the plasma membrane, which provides “eat-me” signals that trigger phagocytosis by macrophages. Mukundan et al. investigated roles for members of the family of peroxisome proliferator-activated receptors (PPARs), which sense fatty acids, in the response of macrophages to apoptotic cells. Exposure of mouse macrophages to apoptotic thymocytes increased the abundance of PPAR-δ mRNA and protein. Macrophages from Ppard–/– mice were less efficient at engulfing apoptotic cells in vitro than were macrophages from wild-type (WT) mice, and injected apoptotic cells were disposed of more quickly in WT mice than they were in Ppard–/– mice. PPAR-δ induced the expression of genes that encode proteins, such as complement component-1qb (C1qb), that opsonize (or coat) target cells to increase the efficiency of phagocytosis. The concentrations of C1qb and other opsonins were lower in the sera of Ppard–/– mice than in the sera of WT mice. Indeed, defects in the phagocytosis of apoptotic cells by macrophages from Ppard–/– mice were rescued by purified human C1q protein. Mice in which Ppard was deleted specifically in macrophages exhibited defects in the phagocytosis of apoptotic cells and developed lupus-like autoimmune responses. Together, these data suggest that PPAR-δ in macrophages senses phospholipids on engulfed apoptotic cells and drives a transcriptional program that enables efficient phagocytosis and inhibits autoimmune responses.
L. Mukundan, J. I. Odegaard, C. R. Morel, J. E. Heredia, J. W. Mwangi, R. R. Ricardo-Gonzalez, Y. P. S. Goh, A. Red Eagle, S. E. Dunn, J. U. H. Awakuni, K. D. Nguyen, L. Steinman, S. A. Michie, A. Chawla, PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat. Med. 15, 1266–1272 (2009). [PubMed]
K. B. Elkon, Autoimmunity: Apoptotic fats grease transcription. Nat. Med. 15, 1246–1248 (2009). [PubMed]