Microglial LOX-1 reacts with extracellular HSP60 to bridge neuroinflammation and neurotoxicity

Neurochem Int. 2012 Dec;61(7):1021-35. doi: 10.1016/j.neuint.2012.07.019. Epub 2012 Jul 27.

Abstract

Chronic neurodegeneration is in part caused by a vicious cycle of persistent microglial activation and progressive neuronal cell loss. However, the driving force behind this cycle remains poorly understood. In this study, we used medium conditioned by necrotic differentiated-PC12 cells to confirm that damaged neurons can release soluble injury signals, including heat shock protein 60 (HSP60), to efficiently promote the neurotoxic cycle involving microglia. Since lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has previously been identified as a novel receptor for HSP60, we hypothesize that LOX-1 through binding to extracellular HSP60 promotes microglia-mediated neuroinflammation. In this study, we observed that LOX-1 expression is induced upon toxic microglial activation, and discovered that LOX-1 is necessary in microglia for sensing soluble neuronal injury signal(s) in the conditioned medium to induce generation of pro-inflammatory mediators (IL-1β, TNF-α, NO and ROS) that promote neurotoxicity. Employing a unique eukaryotic HSP60-overexpression method, we further demonstrated that extracellular HSP60 acts on microglial LOX-1 to boost the production of pro-inflammatory factors (IL-1β, NO and ROS) in microglia and to propagate neuronal damage. These results indicate that LOX-1 is essential in microglia for promoting an inflammatory response in the presence of soluble neuronal-injury signals such as extracellular HSP60, thereby linking neuroinflammation and neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Chaperonin 60 / metabolism*
  • Culture Media, Conditioned
  • DNA Primers
  • Encephalitis / metabolism*
  • Microglia / enzymology*
  • PC12 Cells
  • RNA Interference
  • Rats
  • Reactive Oxygen Species / metabolism
  • Scavenger Receptors, Class E / metabolism*

Substances

  • Chaperonin 60
  • Culture Media, Conditioned
  • DNA Primers
  • OLR1 protein, rat
  • Reactive Oxygen Species
  • Scavenger Receptors, Class E