Loss of PPARα perpetuates sex differences in stroke reflected by peripheral immune mechanisms

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor transcription factor that plays a role in immune regulation. Because of its expression in cerebral tissue and immune cells, PPAR alpha has been examined as an important regulator in immune-based neurological diseases. Many studies have indicated that pre-treatment of animals with PPAR alpha agonists induces protection against stroke. However, our previous reports indicate that protection is only in males, not females, and can be attributed to different PPAR alpha expression between the sexes. In the current study, we examine how loss of PPAR alpha affects male and female mice in experimental stroke. Male and female PPAR alpha knockout mice were subject to middle cerebral artery occlusion (MCAO) or sham surgery, and the ischemic (local) or spleen specific (peripheral) immune response was examined 96 h after reperfusion. We found that loss of PPAR alpha perpetuated sex differences in stroke, and this was driven by the peripheral, not local, immune response. Specifically we observed an increase in peripheral pro-inflammatory and adhesion molecule gene expression in PPAR alpha KO males after MCAO compared to females. Our data supports previous evidence that PPAR alpha plays an important role in sex differences in the immune response to disease, including stroke.