Pro-inflammatory cytokine-mediated ferroportin down-regulation contributes to the nigral iron accumulation in lipopolysaccharide-induced Parkinsonian models

Abstract

Pro-inflammatory cytokines induced by inflammation and iron accumulation in the substantia nigra (SN) have been implicated in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to investigate the relationship between inflammation and iron accumulation in a lipopolysaccharide (LPS)-induced Parkinsonian rat model. The activation of glial cells and elevated levels of pro-inflammatory cytokines were observed in the SN of LPS models, accompanied by iron deposits in the same region. Moreover, ferroportin (Fpn), the only channel for iron export, was down-regulated. SH-SY5Y dopaminergic cells were pre-incubated with conditioned media enriched in pro-inflammatory cytokines, and abnormal iron deposits and a drop of Fpn were observed. The expression of heme oxygenase-1 (HO-1) was also upregulated in vivo and in vitro. These results suggested that pro-inflammatory cytokines might induce Fpn downregulation, which leads to iron accumulation and dopaminergic neurons' degeneration in PD. HO-1 may also contribute to the iron accumulation in neurons, but its mechanism needs to be further investigated.

Keywords: CM; Ct; ELISA; Fpn; HE; HO-1; IL; LPS; PBS; PD; Parkinson’s disease; RT-PCR; SDS–PAGE; SN; SS; TH; TNF-α; conditioned media; cycle time; enzyme-linked immunosorbent assay; ferroportin; hematoxylin and eosin; heme oxygenase-1; inflammation; interleukin; iron accumulation; lipopolysaccharide; phosphate-buffered saline; pro-inflammatory cytokine; reverse transcription polymerase chain reaction; sodium dodecyl sulfate–polyacrylamide gel electrophoresis; sodium salicylate; substantia nigra; tumor necrosis factor-α; tyrosine hydroxylase.