TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning

Amy E B Packard, Philberta Y. Leung, Keri B. Vartanian, Susan L. Stevens, Frances Bahjat, Mary Stenzel-Poore

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF.

Original languageEnglish (US)
Pages (from-to)2193-2200
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume32
Issue number12
DOIs
StatePublished - Dec 2012

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Tumor Necrosis Factor-alpha
Bone Marrow
Brain
Phenotype
Messenger RNA
Neuroprotection
Brain Injuries
Radiation
Ligands

Keywords

  • acute stroke
  • brain ischemia
  • focal ischemia
  • ischemic preconditioning and induced neuroprotection
  • neuroprotection

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Cite this

TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning. / Packard, Amy E B; Leung, Philberta Y.; Vartanian, Keri B.; Stevens, Susan L.; Bahjat, Frances; Stenzel-Poore, Mary.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 32, No. 12, 12.2012, p. 2193-2200.

Research output: Contribution to journalArticle

Packard, Amy E B ; Leung, Philberta Y. ; Vartanian, Keri B. ; Stevens, Susan L. ; Bahjat, Frances ; Stenzel-Poore, Mary. / TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning. In: Journal of Cerebral Blood Flow and Metabolism. 2012 ; Vol. 32, No. 12. pp. 2193-2200.
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