Endotoxin preconditioning protects against the cytotoxic effects of TNFα after stroke: A novel role for TNFα in LPS-ischemic tolerance

Holly Rosenzweig, Manabu Minami, Nikola S. Lessov, Sarah C. Coste, Susan L. Stevens, David C. Henshall, Robert Meller, Roger P. Simon, Mary Stenzel-Poore

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-α (TNFα) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFα in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFα are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFα before middle cerebral artery occlusion in mice and show that TNFα is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFα are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFα (∼threefold) and the proximal TNFα signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (∼2.5-fold), which may neutralize the effect of TNFα and reduce TNFα-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFα after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFα in the setting of ischemia. Our studies suggest that TNFα is a twin-edged sword in the setting of stroke: TNFα upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFα signaling during ischemia confers neuroprotection after LPS preconditioning.

Original languageEnglish (US)
Pages (from-to)1663-1674
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number10
DOIs
StatePublished - Oct 2007

Fingerprint

Endotoxins
Lipopolysaccharides
Tumor Necrosis Factor-alpha
Stroke
Ischemia
Tumor Necrosis Factor Receptors
Wounds and Injuries
Middle Cerebral Artery Infarction
Brain Injuries
Up-Regulation

Keywords

  • Cerebral ischemia
  • Endotoxin
  • Ischemic tolerance
  • Neuroprotection
  • Preconditioning
  • TNFα

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Endotoxin preconditioning protects against the cytotoxic effects of TNFα after stroke : A novel role for TNFα in LPS-ischemic tolerance. / Rosenzweig, Holly; Minami, Manabu; Lessov, Nikola S.; Coste, Sarah C.; Stevens, Susan L.; Henshall, David C.; Meller, Robert; Simon, Roger P.; Stenzel-Poore, Mary.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. 10, 10.2007, p. 1663-1674.

Research output: Contribution to journalArticle

Rosenzweig, Holly ; Minami, Manabu ; Lessov, Nikola S. ; Coste, Sarah C. ; Stevens, Susan L. ; Henshall, David C. ; Meller, Robert ; Simon, Roger P. ; Stenzel-Poore, Mary. / Endotoxin preconditioning protects against the cytotoxic effects of TNFα after stroke : A novel role for TNFα in LPS-ischemic tolerance. In: Journal of Cerebral Blood Flow and Metabolism. 2007 ; Vol. 27, No. 10. pp. 1663-1674.
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T2 - A novel role for TNFα in LPS-ischemic tolerance

AU - Rosenzweig, Holly

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AU - Lessov, Nikola S.

AU - Coste, Sarah C.

AU - Stevens, Susan L.

AU - Henshall, David C.

AU - Meller, Robert

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N2 - Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-α (TNFα) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFα in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFα are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFα before middle cerebral artery occlusion in mice and show that TNFα is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFα are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFα (∼threefold) and the proximal TNFα signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (∼2.5-fold), which may neutralize the effect of TNFα and reduce TNFα-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFα after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFα in the setting of ischemia. Our studies suggest that TNFα is a twin-edged sword in the setting of stroke: TNFα upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFα signaling during ischemia confers neuroprotection after LPS preconditioning.

AB - Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-α (TNFα) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFα in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFα are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFα before middle cerebral artery occlusion in mice and show that TNFα is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFα are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFα (∼threefold) and the proximal TNFα signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (∼2.5-fold), which may neutralize the effect of TNFα and reduce TNFα-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFα after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFα in the setting of ischemia. Our studies suggest that TNFα is a twin-edged sword in the setting of stroke: TNFα upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFα signaling during ischemia confers neuroprotection after LPS preconditioning.

KW - Cerebral ischemia

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