Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2

J Biol Chem. 2009 Feb 6;284(6):3691-9. doi: 10.1074/jbc.M804446200. Epub 2008 Dec 17.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damages neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q, or G10V mutant, as compared with the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-alpha (TNF-alpha), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-alpha secretion at a post-transcriptional level and involved ROS-sensitive TNF-alpha-converting enzymes, e.g. ADAM10 and -17, which shed TNF-alpha from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / immunology
  • ADAM Proteins / metabolism
  • ADAM10 Protein
  • ADAM17 Protein
  • Amino Acid Substitution / immunology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / immunology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyotrophic Lateral Sclerosis / ethnology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / immunology
  • Cell Death / immunology
  • Cell Line
  • Humans
  • Immunity, Innate / genetics
  • Inflammation / enzymology
  • Inflammation / genetics
  • Inflammation / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Microglia / enzymology*
  • Microglia / immunology
  • Mutation, Missense* / immunology
  • NADPH Oxidases / genetics
  • NADPH Oxidases / immunology
  • NADPH Oxidases / metabolism
  • Neurons / enzymology
  • Neurons / immunology
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / immunology
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Membrane Proteins
  • Reactive Oxygen Species
  • SOD1 protein, human
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • NADPH Oxidases
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein