Heat shock protein 70 suppresses neuroinflammation induced by α-synuclein in astrocytes

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Neuroinflammation triggered by activation of glial cells plays an important role in the pathophysiology of several neurodegenerative diseases including Parkinson's disease (PD). Besides microglia, astrocytes are also critical in initiating and perpetuating inflammatory process associated with PD. Heat shock protein 70 (Hsp70) is originally described as intracellular chaperone, however, recent study revealed that it had anti-inflammatory effects as well. The present study is designed to investigate whether Hsp70 mediates neuroinflammation in astrocytes. By employing α-synuclein (α-Syn) (A53T) aggregates on primary cultured astrocytes of rats, we found that astrocytes were activated and neuroinflammatory response was triggered, as indicated by over-expression of glial fibrillary acidic protein (GFAP), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), increased production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The data also showed that the neuroinflammatory response accompanied up-regulated Hsp70 expression. Moreover, over-expression of Hsp70 through transfection of Hsp70 cDNA plasmids could significantly reduce the production of TNF-α, IL-1β, and the expression of GFAP, COX-2 as well as iNOS. While inhibition of Hsp70 by VER155008 exacerbated neuroinflammatory response in astrocytes challenged by α-Syn aggregates. Further mechanistic study indicated that c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) signalings were responsible for the neuroinflammation, which was also regulated by Hsp70. These findings demonstrated that Hsp70 was an important modulator in astrocytes induced inflammation, and up-regulation of Hsp70 might be a potential regulating approach for neuroinflammation-related neurodegenerative diseases, such as PD.Highlightsα-Synuclein triggers neuroinflammatory response in astrocytes.Up-regulation of Hsp70 attenuates neuroinflammation in astrocytes.Inhibition of Hsp70 exacerbates neuroinflammation in astrocytes.Hsp70 regulates neuroinflammation through inhibiting JNK and NF-κB signaling pathways.

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