Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

Pernille M. Madsen, Bettina H. Clausen, Matilda Degn, Stine Thyssen, Lotte K. Kristensen, Martina Svensson, Nicholas Ditzel, Bente Finsen, Tomas Deierborg, Roberta Brambilla, Kate L. Lambertsen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factor ' "/' " compared to membrane-anchored tumor necrosis factor wt/wt mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factor ' "/' " mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy.

Original languageEnglish (US)
Pages (from-to)1553-1569
Number of pages17
JournalJournal of Cerebral Blood Flow and Metabolism
Volume36
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Brain Ischemia
Tumor Necrosis Factor-alpha
Membranes
Stroke
Neuroprotection
Interleukin-1
Interleukin-6
Chemokine CXCL10
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Cytokines
Chemokine CCL2
Microglia
Knockout Mice

Keywords

  • behavior
  • chemokines
  • cytokines
  • macrophages
  • microglia
  • neuroprotection
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Medicine(all)
  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia. / Madsen, Pernille M.; Clausen, Bettina H.; Degn, Matilda; Thyssen, Stine; Kristensen, Lotte K.; Svensson, Martina; Ditzel, Nicholas; Finsen, Bente; Deierborg, Tomas; Brambilla, Roberta; Lambertsen, Kate L.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 36, No. 9, 01.09.2016, p. 1553-1569.

Research output: Contribution to journalArticle

Madsen, Pernille M. ; Clausen, Bettina H. ; Degn, Matilda ; Thyssen, Stine ; Kristensen, Lotte K. ; Svensson, Martina ; Ditzel, Nicholas ; Finsen, Bente ; Deierborg, Tomas ; Brambilla, Roberta ; Lambertsen, Kate L. / Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia. In: Journal of Cerebral Blood Flow and Metabolism. 2016 ; Vol. 36, No. 9. pp. 1553-1569.
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AU - Thyssen, Stine

AU - Kristensen, Lotte K.

AU - Svensson, Martina

AU - Ditzel, Nicholas

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AU - Lambertsen, Kate L.

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AB - Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factor ' "/' " compared to membrane-anchored tumor necrosis factor wt/wt mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factor ' "/' " mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy.

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