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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.

SUBMITTER: Shintani Y 

PROVIDER: S-EPMC3612600 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Shintani Yasunori Y   Kapoor Amar A   Kaneko Masahiro M   Smolenski Ryszard T RT   D'Acquisto Fulvio F   Coppen Steven R SR   Harada-Shoji Narumi N   Lee Hack Jae HJ   Thiemermann Christoph C   Takashima Seiji S   Yashiro Kenta K   Suzuki Ken K  

Proceedings of the National Academy of Sciences of the United States of America 20130311 13


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 cell  ...[more]

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