Deficient phagocytic clearance of apoptotic cells by macrophages is one pathway that has been suggested to contribute to the pathogenesis of lupus. In healthy individuals, macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses to apoptotic debris. Scientists at Stanford University School of Medicine have now shown that the nuclear receptor, peroxisome proliferator-activated receptor-δ (PPAR-δ) plays a pivotal role in orchestrating phagocytosis. Genetically engineered mice lacking PPAR-δ showed decreased expression of opsonins, resulting in impaired clearance of apoptotic cells and reduced levels of anti-inflammatory cytokines. Both global and macrophage-specific Ppard-/- mice showed increased production of autoantibodies and were predisposed to autoimmune kidney disease, a condition resembling one of the manifestations of human lupus. PPAR-δ agonists are being investigated for the treatment of metabolic disorders such as hyperlipidemia, diabetes and obesity and the authors suggest that such compounds could also potentially benefit lupus sufferers.
The study was published online on October 18th in the journal Nature Medicine.