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Toll-like receptor 9 signaling after myocardial infarction: Role of p66ShcA adaptor protein

Anton Baysa1, Azzam A Maghazachi1, Kristin Larsen Sand1

  • 1Department of Molecular Medicine, Institute of Basic Medical Science University of Oslo, Norway.

Biochemical and Biophysical Research Communications
|January 12, 2023
PubMed

Insights

The p66ShcA adaptor protein interacts with Toll-like receptor 9 (TLR9), amplifying inflammation after heart attack. Blocking p66ShcA reduces this immune response, offering a potential therapeutic target for myocardial infarction.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Molecular Medicine

Background:

  • Myocardial infarction (MI) triggers sterile inflammation via pattern recognition receptors, exacerbating damage and leading to heart failure.
  • Toll-like receptor 9 (TLR9) detects endogenous DNA fragments, initiating inflammatory responses mediated by NFκB.
  • The p66ShcA adaptor protein is implicated in both ischemic injury and immune modulation.

Purpose of the Study:

  • To investigate the role of the p66ShcA adaptor protein in regulating DNA-sensing signaling through the TLR9 pathway following myocardial infarction.
  • To determine if p66ShcA influences TLR9 expression and activation in the context of cardiac ischemia.

Main Methods:

  • Analysis of TLR9 protein expression in human heart failure tissue.
  • Induction of myocardial ischemia in p66ShcA knockout and wild-type mice.
  • Assessment of TLR9 pathway gene expression (MyD88, Unc93b1) post-ischemia.
  • In vitro studies using NFκB reporter cells and cardiac fibroblasts to examine p66ShcA-TLR9 interactions.
  • Co-immunoprecipitation and proximity assays to confirm protein complex formation.
  • Measurement of systemic inflammatory markers (interleukins) in knockout mice.

Main Results:

  • TLR9 expression was elevated in cardiac tissue from patients with ischemic heart failure.
  • Myocardial ischemia in mice upregulated key TLR9 pathway components.
  • p66ShcA deficiency abrogated ischemia-induced TLR9 upregulation and dampened systemic inflammation.
  • Overexpression of p66ShcA enhanced TLR9-mediated NFκB activation and increased TLR9 expression in cardiac fibroblasts.
  • Co-immunoprecipitation and proximity assays confirmed physical interaction between ShcA proteins and TLR9.

Conclusions:

  • p66ShcA adaptor protein plays a crucial role in promoting TLR9-mediated inflammatory signaling after myocardial infarction.
  • p66ShcA may act as a regulator and interaction partner of the TLR9 pathway in the post-infarction cardiac environment.
  • Targeting the p66ShcA-TLR9 interaction could represent a novel therapeutic strategy to mitigate inflammation and secondary damage following MI.

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