Rifampicin attenuates rotenone-treated microglia inflammation via improving lysosomal function

Mounting evidence suggests that lysosome dysfunction promotes the progression o f several neurodegenerative diseases via hampering autophagy flux. While regulation o f autophagy in microglia may affect chronic inflammation involved in Parkinson's disease (PD). Our previous studies have reported rifampicin inhibits rote- none-induced microglia inflammation by enhancing autophagy, however the precise mechanism remains unclear. Human microglia (HM) cells were pretreated with 1 00 mu M rifampicin for 2 h followed by exposure to 0.1 mu M rotenone. We found that rifampicin pretreatment suppressed the gene expression o f IL-1 beta and IL-6 via inhibiting activation of JNK after rotenone induction, but the anti-inflammatory effect o f rifampicin was reversed by chloroquine. Moreover, rifampicin pretreatment not only improved the ratio o f LC3-II/LC3-I in rotenone-treated cells, but also increased autolysosomes and decreased autophagosomes in RFP-GFP-LC3B transfected HM cells exposed to rotenone, thus indicating rifampicin improves autophagy flux in rotenone- treated HM cells. Finally, we verified rifampicin pretreatment enhanced ATP6V0A1 expression when compared to that exposed to rotenone alone. ATP6V0A1 knockdown inhibited the effect o f rifampicin on maintaining lysosome acidification and autophagosome-lysosome fusion in rotenone-treated microglia. Taken together, our results indicated that rifampicin attenuates rotenone-induced microglia inflammation partially via elevating ATP6V0A1. Modulation of lysosomal function by rifampicin may be a novel therapeutic strategy for PD.