Peroxiredoxins and the Pro-inflammatory Immune Response in Drosophila

Accumulating evidence suggests that compromised redox signaling enhances the development of hyperactive, pro-inflammatory immune response, which ultimately reduces health- and lifespan. Either underexpression of Peroxiredoxins in the mitochondria (dPrx3 and dPrx5) or overexpression in the ER (dPrx4) has life span shortening effects. Here we show that these effects are associated with activation of the NF-κB –dependent immunity-related/inflammatory genes, which are normally induced in response to infection and ER stress, and constitutively overproduced in old animals. In transgenic flies expressing the ER-localized dPrx4 in the absence of Relish, a Drosophila NF-κB ortholog, the pro-inflammatory effects typically elicited by dPrx4 overexpression were absent. The absence of Relish also significantly rescued the severe shortening of lifespan normally observed in dPrx4 overexpressors. Epistatic analysis also revealed that the dPrx-4 driven overactivation of immune/inflammatory responses was mediated by JAK/STAT signaling. Finally we determined that the activity of dPrx4 in the ER is required to mediate the pro-inflammatory response caused by reduced Prx activity in mitochondria. Thus this study provides evidence for cross-talk between the ER- and mitochondrially-localized peroxiredoxins in regulating the immune response.