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

Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5109-14. doi: 10.1073/pnas.1219243110. Epub 2013 Mar 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Adenosine Monophosphate / genetics
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cells, Cultured
  • Energy Metabolism / physiology*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Protein Transport / physiology
  • Rats
  • Rats, Wistar
  • Signal Transduction / physiology
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / metabolism*


  • Membrane Transport Proteins
  • Muscle Proteins
  • Nerve Tissue Proteins
  • Tlr9 protein, mouse
  • Tlr9 protein, rat
  • Toll-Like Receptor 9
  • UNC93B1 protein, mouse
  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • AMP-Activated Protein Kinases