Extracellular Hsp90α stimulates a unique innate gene profile in microglial cells with simultaneous activation of Nrf2 and protection from oxidative stress

Yuka Okusha, Benjamin J. Lang, Ayesha Murshid, Thiago J. Borges, Kristina M. Holton, Joanne Clark-Matott, Sachin Doshi, Tsuneya Ikezu, Stuart K. Calderwood

Research output: Contribution to journalArticlepeer-review

Abstract

Delivery of exogenous heat shock protein 90α (Hsp90α) and/or its induced expression in neural tissues has been suggested as a potential strategy to combat neurodegenerative disease. However, within a neurodegenerative context, a pro-inflammatory response to extracellular Hsp90α (eHsp90α) could undermine strategies to use it for therapeutic intervention. The aim of this study was to investigate the biological effects of eHsp90α on microglial cells, the primary mediators of inflammatory responses in the brain. Transcriptomic profiling by RNA-seq of primary microglia and the cultured EOC2 microglial cell line treated with eHsp90α showed the chaperone to stimulate activation of innate immune responses in microglia that were characterized by an increase in NF-kB-regulated genes. Further characterization showed this response to be substantially lower in amplitude than the effects of other inflammatory stimuli such as fibrillar amyloid-β (fAβ) or lipopolysaccharide (LPS). Additionally, the toxicity of conditioned media obtained from microglia treated with fAβ was attenuated by addition of eHsp90α. Using a co-culture system of microglia and hippocampal neuronal cell line HT22 cells separated by a chamber insert, the neurotoxicity of medium conditioned by microglia treated with fAβ was reduced when eHsp90α was also added. Mechanistically, eHsp90α was shown to activate Nrf2, a response which attenuated fAβ-induced nitric oxide production. The data thus suggested that eHsp90α protects against fAβ-induced oxidative stress. We also report eHsp90α to induce expression of macrophage receptor with collagenous structure (Marco), which would permit receptor-mediated endocytosis of fAβ.

Original languageEnglish (US)
JournalCell Stress and Chaperones
DOIs
StateAccepted/In press - 2022

Keywords

  • Amyloid-beta
  • Extracellular HSPs
  • Hsp90
  • Inflammation
  • Marco
  • Microglia
  • NF-kB
  • Nrf2

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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