"We wanted to know, if you took a mouse and only deleted PPAR-delta from its macrophages, is that sufficient to cause an autoimmune disease?" Chawla said. "Apparently it is."
To test their theory, researchers bred genetically engineered mice that were missing the PPAR-delta molecule in their macrophages, and then injected them with apoptotic (dying) cells. It turned out that simply missing the PPAR-delta molecule caused a lupuslike autoimmune kidney disorder in mice.
Drugs that activate PPAR-delta have been identified and are in clinical trials for treatment of high blood cholesterol and other lipid disorders. Thus, the direct involvement of PPAR-delta in suppressing autoantibody production and maintaining the body's tolerance to itself raises the possibility that these molecules that activate PPAR-delta can be used to treat patients with lupus.
The study pinpoints how PPAR-delta works in macrophages. When the macrophages eat dying cells, certain genes get turned on in these cells, triggering further consumption of more dying cells and aiding in their clearance.
First, PPAR-delta aids in the recognition of the dying cell by regulating the production of key proteins called opsonins. These proteins recognize the "eat me" signals released by the dying cells. In addition, PPAR-delta also prevents the immune system from mounting an inflammatory response to the dying cell and thus functions in the safe disposal of the dying cells. In the absence of PPAR-delta, mice have an accumulation of dead cells that over time delivers a danger signal to the immune system, leading to inflammation and tissue damage.
"The dying cells are a bunch of modified lipids," Chawla noted.
When the macrophages eat the dying cells it doubles their content of lipids. The team showed in additional experiments in the lab that the lipids worked as a signal t
|Contact: Tracie White|
Stanford University Medical Center