MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity

Zhong Pei, Hao Pang, Li Qian, Sufen Yang, Tonggauang Wang, Wei Zhang, Xeufei Wu, Shannon Dallas, Belinda Wilson, Jeffrey M. Reece, David S. Miller, Jau Shyong Hong, Michelle L. Block

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Microglia-derived superoxide is critical for the inflammation-induced selective loss of dopaminergic (DA) neurons, but the underlying mechanisms of microglial activation remain poorly defined. Using neuron-glia and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1 -/-), we demonstrate that lipopolysaccharide (LPS) treatment results in lower TNFα response, attenuated loss of DA neurons, and absence of extracellular superoxide production in MAC1-/- cultures. Microglia accumulated fluorescently labeled LPS in punctate compartments associated with the plasma membrane, intracellular vesicles, and the Golgi apparatus. Cytochalasin D (CD), an inhibitor of phagocytosis, blocked LPS internalization. However, microglia derived from Toll-like receptor 4 deficient mice and MAC1-/- mice failed to show a significant decrease in intracellular accumulation of labeled LPS, when compared with controls. Pretreatment with the scavenger receptor inhibitor, fucoidan, inhibited 79% of LPS accumulation in microglia without affecting superoxide, indicating that LPS internalization and superoxide production are mediated by separate phagocytosis receptors. Together, these data demonstrate that MAC1 is essential for LPS-induced superoxide from microglia, implicating MAC1 as a critical trigger of microglial-derived oxidative stress during inflammation-mediated neurodegeneration.

Original languageEnglish (US)
Pages (from-to)1362-1373
Number of pages12
JournalGlia
Volume55
Issue number13
DOIs
StatePublished - Oct 2007

Keywords

  • Dopaminergic neurotoxicity
  • LPS
  • MAC1
  • Microglia
  • Phagocytosis
  • Reactive oxygen species
  • Superoxide

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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