A Parkinson's disease gene, DJ-1, regulates anti-inflammatory roles of astrocytes through prostaglandin D2 synthase expression

Abstract

Dysfunctional regulation of inflammation may contribute to the progression of neurodegenerative diseases. The results of this study revealed that DJ-1, a Parkinson's disease (PD) gene, regulated expression of prostaglandin D2 synthase (PTGDS) and production of prostaglandin D2 (PGD2), by which DJ-1 enhanced anti-inflammatory function of astrocytes. In injured DJ-1 knockout (KO) brain, expression of tumor necrosis factor-alpha (TNF-alpha) was more increased, but that of anti-inflammatory heme oxygenase-1 (HO-1) was less increased compared with that in injured wild-type (WT) brain. Similarly, astrocyte-conditioned media (ACM) prepared from DJ-1-KO astrocytes less induced HO-1 expression and less inhibited expression of inflammatory mediators in microglia. With respect to the underlying mechanism, we found that PTGDS that induced expression of HO-1 was lower in DJ-1 KO astrocytes and brains compared with their WT counterparts. In addition, PTGDS levels increased in the injured brain of WT mice, but barely in that of KO mice. We also found that DJ-1 regulated PTGDS expression through Sox9. Thus, Sox9 siRNAs reduced PTGDS expression in WT astrocytes, and Sox9 overexpression rescued PTGDS expression in DJ-1 KO astrocytes. In agreement with these results, ACM from Sox9 siRNA-treated astrocytes and that from Sox9-overexpression astrocytes exerted opposite effects on HO-1 expression and anti-inflammation. These findings suggest that DJ-1 positively regulates anti-inflammatory functions of astrocytes, and that DJ-1 dysfunction contributes to the excessive inflammatory response in PD development.