Foxp3 is a novel repressor of microglia activation.

Forkhead transcription factor 3 (Foxp3) is critical for generating CD4(+)CD25(+) regulatory T cells. However, its role in microglia has not been identified. Here, we show that Foxp3 is expressed in microglia and is upregulated upon activation. In Foxp3 mutant mice (Foxp3(sf)), microglia release higher levels of inflammatory cytokines and mediators such as NO, MCP-1, CXCL10, and ROS upon liposaccharide treatment than the wild type, while TNF-alpha and IL-1 beta were not significantly different between wild and mutant microglial cells. In addition, Foxp3 silencing enhances inflammatory responses, suggesting that the major role of Foxp3 in microglia is that of a repressor of activation. Similarly, Foxp3 overexpression reduces inflammatory responses in microglia. We also demonstrate that Foxp3 interacts directly with NF-kappaB and modulates its transcriptional activities. These findings point to the importance of Foxp3 in NF-kappaB mediated inflammatory responses in microglia.