title: TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons.
abstract: 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.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom. y.shintani@qmul.ac.uk
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Amar
authors.initials: A
authors.lastname: Kapoor
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneko
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
authors.forename: Fulvio
authors.initials: F
authors.lastname: D'Acquisto
authors.forename: Steven R
authors.initials: SR
authors.lastname: Coppen
authors.forename: Narumi
authors.initials: N
authors.lastname: Harada-Shoji
authors.forename: Hack Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Kenta
authors.initials: K
authors.lastname: Yashiro
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C495370:Tlr9 protein, mouse; C489640:Tlr9 protein, rat; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases