Editors' ChoicePhysiology

Protecting the Heart and Mind from Stress

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Science Signaling  02 Apr 2013:
Vol. 6, Issue 269, pp. ec77
DOI: 10.1126/scisignal.2004196

Toll-like receptors (TLRs) initiate the inflammatory response in immune cells. TLR9 is present in immune cells and some nonimmune cells, including cardiomyocytes and neurons, and it recognizes DNA from either bacterial cells or injured host cells. Shintani et al. found that TLR9 may function in an alternate, noninflammatory signaling pathway in cardiomyocytes and neurons to protect them from damaging inflammation. Administration of CpG oligodendronucleotide (CpG-ODN), a synthetic TLR9 ligand, into ex vivo beating hearts from wild-type or TLR9-deficient mice rapidly reduced cardiac contractility and energy metabolism markers and increased the activity of adenosine monophosphate–activated protein kinase (AMPK) only in wild-type hearts. Similar metabolic changes were seen in a differentiated neuronal cell line as well as in the hearts of mice deficient in MyD88 (myeloid differentiation primary response gene 88), an adaptor protein that is required for TLR9 signaling in immune cells. Furthermore, markers of the canonical inflammatory response, including activation of NF-κB (nuclear factor κB) and mitogen-activated protein kinase signaling, were detected in a macrophage cell line in response to CpG-ODN but not in cardiomyocytes. The expression of Unc93b1, a gene encoding a key molecule that translocates TLR9 from the endoplasmic reticulum (ER) to the endosomes to initiate inflammatory signaling with MyD88, was decreased in cardiomyocytes compared with macrophages, and both the endosomal translocation of TLR9 and its interaction with MyD88 were detected only in macrophages. Depletion of Unc93b1 in macrophages treated with CpG-ODN reduced the inflammatory response and increased the activation of AMPK, whereas the overexpression of Unc93b1 in cardiomyocytes induced the translocation of TLR9, enhanced inflammatory signaling, and decreased the activity of AMPK. In wild-type cardiomyocytes, CpG-ODN translocated from endosomes to the ER through retrograde signaling to bind to TLR9. Treatment with Retro-2, an inhibitor of retrograde transport, restricted the localization of CpG-ODN to the endosomes and reduced the TLR9-dependent activation of AMPK both in cardiomyocytes and in Unc93b1-deficient macrophages. Together, these findings suggest that after tissue injury the same TLR9-ligand interaction can independently induce either inflammation or a protective reduction in metabolism depending on cell-type–specific trafficking.

Y. Shintani, A. Kapoor, M. Kaneko, R. T. Smolenski, F. D’Acquisto, S. R. Coppen, N. Harada-Shoji, H. J. Lee, C. Thiemermann, S. Takeshima, K. Yashiro, K. Suzuki, TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc. Natl. Acad. Sci. U.S.A. 110, 5109–5114 (2013). [Abstract] [Full Text]