PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance

Lata. M. et al. 2009. Nat. Med. 15, 1266-1272

Speaker: Yu-Hong Chen (陳俞宏)                        Time: 13:10~14:00, Mar. 10, 2010

Commentator: Dr. Li-Jin Hsu (徐麗君老師)        Place: Room 601

Abstract:

Clearance of the apoptotic cells by macrophages avoids arising some autoimmune disease, like systemic lupus erythematosus (SLE) in vertebrates (1). Engulfment of the cell corpse by phagocytosis brings large amounts of cellular lipid, including oxidized fatty acids and oxysterols, into macrophages. The genetic sensor of native and oxidized fatty acids, nuclear receptor peroxisome proliferator–activated receptors (PPARs), can activate macrophages (2, 3). The authors postulate these lipid sensors contribute to apoptotic cell clearance by macrophages and promote self tolerance. First, the expression of PPAR-δ in mouse bone marrow-derived macrophages (BMDMs) was induced after feeding apoptotic cells to the macrophages. Using Ppard ^−/− mice, they found that PPAR-δ promoted timely disposal of dying cells in macrophages by flow cytometric analysis. Next, they used microarray analysis and found that knockout of PPAR-δ reduced expression of some opsonins, which serve as a bridge to link apoptotic cells to macrophage cell surface receptors. Stimulation of PPAR-δ agonist GW0742 enhanced the gene expression of some opsonins, such as complement component 1, q subcomponent, B chain (C1qb). After that, they treated primary human monocyte-derived macrophages with GW0742 and incubated macrophages from Ppard ^−/− mice with serum of WT mice to know that PPAR-δ promptly orchestrates the apoptotic cells in mouse and human macrophages by inducing expression of opsonins. Then, knockout of PPAR-d diminished apoptotic cell-induced immunosuppressive effects, such as opsonins expression, phagocytosis of macrophage and IL-10 expression. Finally, the authors found out Ppard ^−/− mice can develop lupus-like autoimmune disease by measuring autoantibody titers in the mice. PPAR-d genetic deficiency in mouse macrophage not only delays clearance of apoptotic cells but also causes accumulation of autoantibodies, leading to collapse the tolerance. In summary, PPAR-δ functions as a sensor of dying cells to orchestrate the phagocytic response when macrophages confront the apoptotic cells.

References:

1. Savill J. et al. 2002. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965-975.

2. Chawla A. et al. 2001. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866-1870.

3. Kang K. et al. 2008. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485-495.