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The Journal of Neuroscience, February 4, 2009, 29(5):1319-1330; doi:10.1523/JNEUROSCI.5505-08.2009

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Cellular/Molecular
Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Kate Lykke Lambertsen,¹ Bettina Hjelm Clausen,¹ Alicia Anne Babcock,¹ Rikke Gregersen,¹ Christina Fenger,¹ Helle Hvilsted Nielsen,¹ Laila Skov Haugaard,^1,2 Martin Wirenfeldt,¹ Marianne Nielsen,³ Frederik Dagnaes-Hansen,⁴ Horst Bluethmann,⁵ Nils Joakim Færgeman,² Michael Meldgaard,¹ Tomas Deierborg,⁶ and Bente Finsen¹

¹Medical Biotechnology Center and Departments of ²Biochemistry and Molecular Biology and ³Anatomy and Neurobiology, University of Southern Denmark, 5000 Odense, Denmark, ⁴Department of Medical Microbiology and Immunology, University of Aarhus, 8000 Aarhus, Denmark, ⁵Transgenic Animal Models, F. Hoffmann-La Roche 93/614, CH-4070 Basel, Switzerland, and ⁶Laboratory of Experimental Brain Research, Lund University, 22184 Lund, Sweden

Correspondence should be addressed to Bente Finsen, Medical Biotechnology Center, Winsloewparken 25, 2, University of Southern Denmark, DK-5000 Odense C, Denmark. Email: bfinsen{at}health.sdu.dk

Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial- not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglial-derived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.

Key words: cytokines; neurodegeneration; knock-out mice; chimeric mice; neuroprotection; behavior

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Received Nov. 12, 2008; accepted Dec. 19, 2008.

Correspondence should be addressed to Bente Finsen, Medical Biotechnology Center, Winsloewparken 25, 2, University of Southern Denmark, DK-5000 Odense C, Denmark. Email: bfinsen{at}health.sdu.dk

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TNF-alpha: Neurotoxic or neuroprotective in stroke

Rao M Adibhatla, et al.

J. Neurosci. Online, 5 Feb 2009 [Full text]

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