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PNAS 110 (13): 5109-5114

Copyright © 2013 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

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

Yasunori Shintania,1, Amar Kapoora, Masahiro Kanekoa, Ryszard T. Smolenskib, Fulvio D’Acquistoa, Steven R. Coppena, Narumi Harada-Shojia, Hack Jae Leea, Christoph Thiemermanna, Seiji Takashimac, Kenta Yashiroa, and Ken Suzukia,1

aWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom; bDepartment of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; and cDepartment of Molecular Cardiology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

Edited* by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved February 15, 2013 (received for review November 6, 2012)

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.


Freely available online through the PNAS open access option.

Author contributions: Y.S. designed research; Y.S., M.K., A.K., R.T.S., N.H.-S., and H.J.L. performed research; F.D., C.T., and S.T. contributed new reagents/analytic tools; Y.S., F.D., S.R.C., S.T., K.Y., and K.S. analyzed data; and Y.S. and K.S. wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1219243110/-/DCSupplemental.

1To whom correspondence may be addressed. E-mail: y.shintani{at}qmul.ac.uk or ken.suzuki{at}qmul.ac.uk.


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