TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons

Yasunori Shintani, Amar Kapoor, Masahiro Kaneko, Ryszard T Smolenski, Fulvio D'Acquisto, Steven R Coppen, Narumi Harada-Shoji, Hack Jae Lee, Christoph Thiemermann, Seiji Takashima, Kenta Yashiro, Ken Suzuki

Research output: Contribution to journalArticlepeer-review


Toll-like receptors (TLRs) are the central players in innate immunity. In particular, TLR9 initiates inflammatory response by recognizing DNA, imported by infection or released from tissue damage. Inflammation is, however, harmful to terminally differentiated organs, such as the heart and brain, with poor regenerative capacity, yet the role of TLR9 in such nonimmune cells, including cardiomyocytes and neurons, is undefined. Here we uncover an unexpected role of TLR9 in energy metabolism and cellular protection in cardiomyocytes and neurons. TLR9 stimulation reduced energy substrates and increased the AMP/ATP ratio, subsequently activating AMP-activated kinase (AMPK), leading to increased stress tolerance against hypoxia in cardiomyocytes without inducing the canonical inflammatory response. Analysis of the expression profiles between cardiomyocytes and macrophages identified that unc93 homolog B1 (C. elegans) was a pivotal switch for the distinct TLR9 responses by regulating subcellular localization of TLR9. Furthermore, this alternative TLR9 signaling was also found to operate in differentiated neuronal cells. These data propose an intriguing model that the same ligand-receptor can concomitantly increase the stress tolerance in cardiomyocytes and neurons, whereas immune cells induce inflammation upon tissue injury.

Original languageEnglish
Pages (from-to)5109-14
Number of pages6
JournalPNAS: Proceedings of the National Academy of Sciences
Issue number13
Publication statusPublished - 26 Mar 2013


  • AMP-Activated Protein Kinases
  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • Animals
  • Caenorhabditis elegans
  • Cells, Cultured
  • Energy Metabolism
  • Inflammation
  • Membrane Transport Proteins
  • Mice
  • Mice, Knockout
  • Muscle Proteins
  • Myocytes, Cardiac
  • Nerve Tissue Proteins
  • Neurons
  • Protein Transport
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Toll-Like Receptor 9
  • Journal Article
  • Research Support, Non-U.S. Gov't

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