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Extracellular DJ-1 induces sterile inflammation in the ischemic brain

Koutarou Nakamura1,2,3, Seiichiro Sakai1,2, Jun Tsuyama1,2

  • 1Stroke Renaissance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Plos Biology
|May 20, 2021
PubMed

Insights

DJ-1 protein, released from dead cells, acts as a damage-associated molecular pattern (DAMP) that triggers inflammation. Neutralizing extracellular DJ-1 reduced inflammation and damage in ischemic stroke models, suggesting it as a therapeutic target.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Inflammation plays a key role in various diseases, including brain pathologies.
  • DJ-1 is an intracellular antioxidant protein with a newly identified extracellular function.
  • Damage-associated molecular patterns (DAMPs) signal cellular damage and initiate inflammatory responses.

Purpose of the Study:

  • To investigate the role of DJ-1 as a damage-associated molecular pattern (DAMP) in inflammation.
  • To identify the mechanism by which DJ-1 triggers inflammation.
  • To evaluate the therapeutic potential of targeting extracellular DJ-1 in cerebral injury.

Main Methods:

  • Recombinant DJ-1 protein was used to stimulate bone marrow-derived macrophages (BMMs) and dendritic cells (BMDCs) to assess cytokine production.
  • A specific peptide sequence in DJ-1 was identified for its ability to activate Toll-like receptor 2 (TLR2) and TLR4.
  • A murine model of middle cerebral artery occlusion (MCAO) was used to study DJ-1 release, immune cell infiltration, and the effects of DJ-1 neutralization via antibody administration.

Main Results:

  • Extracellular DJ-1 induced the production of inflammatory cytokines in immune cells.
  • A peptide sequence in DJ-1's αG and αH helices was found to activate TLR2 and TLR4.
  • In MCAO models, DJ-1 was released from necrotic neurons and interacted with TLR2 and TLR4 on infiltrating myeloid cells.
  • DJ-1 deficiency reduced inflammatory cytokine expression in immune cells post-stroke.
  • Antibody-mediated neutralization of extracellular DJ-1 suppressed post-ischemic inflammation and attenuated neuronal damage.

Conclusions:

  • DJ-1 functions as a damage-associated molecular pattern (DAMP) that promotes inflammation when released extracellularly.
  • Extracellular DJ-1 activates TLR2 and TLR4, contributing to neuroinflammation after ischemic stroke.
  • Targeting extracellular DJ-1 represents a potential therapeutic strategy for mitigating inflammation in tissue injuries and neurodegenerative diseases.

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