We may rarely think about it, but millions of our cells die every day. If not properly disposed of, they rupture and expose surrounding cells to their toxic contents, often prompting an autoimmune response against healthy neighboring cells. That's what lupus essentially is – a defect in the body's waste disposal system. Mopping up dead (apoptotic) cells is the job of macrophages. This important role has been known for some time, but the transcription factors that coordinate it were not. In 2010, a collaborative research group comprised of scientists from Stanford University School of Medicine and Baylor University determined that one of those factors is peroxisome proliferator-activated receptor-delta (PPARD) (Mukundan et al. 2009).
The authors suspected that PPARs played a key role in directing macrophages to clear apoptotic cells because PPARs are genetic sensors of oxidized fatty acids, which are present in large amounts in apoptotic cells. The authors found that, of three mouse PPARs (PPARA, PPARG, and PPARD), only PPARD is induced when macrophages engulf apoptotic cells. They also found that Ppard-deficient macrophages produce few opsonins (proteins that help macrophages recognize and engulf apoptotic cells), impairing apoptotic cell clearance and reducing the production of anti-inflammatory cytokines. In mice with Ppard-deficient macrophages, this constellation of events increases autoantibody production and leads to lupus-like autoimmune kidney disease. These findings led the authors to conclude that PPARD helps macrophages to sense and to dispose of apoptotic cells and helps to maintain self-tolerance. The findings also indicate that Ppard-deficient mice are a promising new model for understanding and developing new therapies for lupus.
JAX® Mice Cre-lox strains used in this study
The authors of this study used the following two JAX® Mice Cre-lox strains: B6.129S4-Ppardtm1Rev/J (005897), which harbors loxP sites on either side of exon 4 of the Ppard gene, and B6.129P2-Lyz2tm1(cre)Ifo/J (004781), which expresses Cre recombinase from the endogenous lysozyme 2 (Lyz2) locus. Offspring produced by mating these two strains have Ppard-deficient macrophages.
Reference
Mukundan L, Odegaard JI, Morel CR, Heredia JE, Mwangi JW, Ricardo-Gonzalez RR, Goh YP, Eagle AR, Dunn SE, Awakuni JU, Nguyen KD, Steinman L, Michie SA, Chawla A. 2009. PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15:1266-72.