Peroxiredoxins and the pro-inflammatory immune response

Accumulating evidence suggests that compromised redox signaling could be responsible for development of hyperactive, pro-inflammatory immune responses, which ultimately affect healthy aging and shorten longevity. Here we show that the lifespan shortening effects observed in flies with altered peroxiredoxin activity in the ER (dPrx4) and mitochondrial (dPrx3 and dPrx5) compartments are associated with activation of the NF-κB –dependent immunity-related/inflammatory genes, which are normally induced in response to infection and constitutively overproduced in old animals. The NF-κB targets could also be activated under conditions of ER stress. 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. Furthermore, the overactivation of immune/inflammatory responses triggered by aberrant dPrx4 activity was mediated by JAK/STAT signaling, as revealed in epistatic analysis using mutants representing the JAK/STAT pathway. We have also found that the proinflammatory response provoked by the oxidant paraquat required dPrx4 activity in the ER, as this response was abrogated in the dprx4 mutant.