Autocrine activation of microglia by tumor necrosis factor-α

Kuno, Reiko; Wang, Jinyan; Koyama, Jun; Takeuchi, Hideyuki; Mizuno, Tetsuya; Suzumura, Akio

doi:10.1016/j.jneuroim.2005.01.015

Cited by 190 publications

(175 citation statements)

References 42 publications

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“…We showed that slices from TNFR2 À/À mice secreted significantly higher levels of TNFa and IL-6 during LPS exposure as compared with slices from WT mice. Similar findings have been observed in cultured microglia by blocking TNFR2 during LPS exposure (Kuno et al, 2005). Thus, signaling through TNFR2 appears to reduce LPS-induced proinflammatory cytokine response resulting in reduced neuronal cell death after LPS and OGD.…”

Section: The Roles Of Tumor Necrosis Factor Receptors 1 and 2 In Liposupporting

confidence: 83%

Tumor Necrosis Factor Receptor-1 is Essential for LPS-Induced Sensitization and Tolerance to Oxygen—Glucose Deprivation in Murine Neonatal Organotypic Hippocampal Slices

Markus

Cronberg

Cilio

et al. 2008

J Cereb Blood Flow Metab

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Inflammation and ischemia have a synergistic damaging effect in the immature brain. The role of tumor necrosis factor (TNF) receptors 1 and 2 in lipopolysaccharide (LPS)-induced sensitization and tolerance to oxygen-glucose deprivation (OGD) was evaluated in neonatal murine hippocampal organotypic slices. Hippocampal slices from balb/c, C57BL/6 TNFR1 À/À , TNFR2 À/À , and wild-type (WT) mice obtained at P6 were grown in vitro for 9 days. Preexposure to LPS immediately before OGD increased propidium iodide-determined cell death in regions CA1, CA3, and dentate gyrus from 4 up to 48 h after OGD (P < 0.001). Extending the time interval between LPS exposure and OGD to 72 h resulted in tolerance, that is reduced neuronal cell death after OGD (P < 0.05). Slices from TNFR1 À/À mice showed neither LPS-induced sensitization nor LPS-induced tolerance to OGD, whereas both effects were present in slices from TNFR2 À/À and WT mice. Cytokine secretion (TNFa and interleukin-6) during LPS exposure was decreased in TNFR1 À/À slices and increased in TNFR2 À/À as compared with WT slices. We conclude that LPS induces sensitization or tolerance to OGD depending on the time interval between exposure to LPS and OGD in murine hippocampal slice cultures. Both paradigms are dependent on signaling through TNFR1.

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Section: The Roles Of Tumor Necrosis Factor Receptors 1 and 2 In Liposupporting

confidence: 83%

Tumor Necrosis Factor Receptor-1 is Essential for LPS-Induced Sensitization and Tolerance to Oxygen—Glucose Deprivation in Murine Neonatal Organotypic Hippocampal Slices

Markus

Cronberg

Cilio

et al. 2008

J Cereb Blood Flow Metab

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“…The number of Iba1 ϩ cells was significantly reduced (by 23%) in TNF-R1 Ϫ/Ϫ mice. The lower cell number in these mice after SE was probably attributable to blockade of TNF-␣-induced microglia proliferation mediated by TNF-R1 (Dopp et al, 1997), possibly through an autocrine mechanism (Kuno et al, 2005). There was no significant correlation between the number of Iba1 ϩ cells and BrdU ϩ /NeuN ϩ cells in the SGZ/GCL of TNF-R1 Ϫ/Ϫ mice after SE (Figs.…”

Section: Deletion Of Tnf-r1 and Tnf-r2 Affects Microglia But Not Astrmentioning

confidence: 87%

Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Iosif

Ekdahl²,

Ahlenius³

et al. 2006

J. Neurosci.

418

290

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Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine, acting through the TNF-R1 and TNF-R2 receptors. The two receptors have been proposed to mediate distinct TNF-␣ effects in the CNS, TNF-R1 contributing to neuronal damage and TNF-R2 being neuroprotective. Whether TNF-␣ and its receptors play any role for neurogenesis in the adult brain is unclear. Here we used mouse models with loss of TNF-R1 and TNF-R2 function to establish whether signaling through these receptors could influence hippocampal neurogenesis in vivo under basal conditions, as well as after status epilepticus (SE), which is associated with inflammation and elevated TNF-␣ levels. Notably, in the intact brain, the number of new, mature hippocampal neurons was elevated in TNF-R1Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice, whereas no significant changes were detected in TNF-R2 Ϫ/Ϫ mice. Also after SE, the TNF-R1 Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice produced more new neurons. In contrast, the TNF-R2 Ϫ/Ϫ mice showed reduced SE-induced neurogenesis. Cell proliferation in the dentate subgranular zone was elevated in TNF-R1 Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice both under basal conditions and after SE. The TNF-R2 Ϫ/Ϫ mice either showed no change or minor decrease of cell proliferation. TNF-R1 and TNF-R2 receptors were expressed by hippocampal progenitors, as assessed with reverse transcription-PCR on sorted or cultured cells and immunocytochemistry on cultures. Our data reveal differential actions of TNF-R1 and TNF-R2 signaling in adult hippocampal neurogenesis and identify for the first time TNF-R1 as a negative regulator of neural progenitor proliferation in both the intact and pathological brain.

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“…In the present in vitro penumbra model, we found that microglia activated by OGD-stressed neurons produced excess TNF-␣, which contributed to killing naive, healthy neurons. In principle, TNF-␣ can act in an autocrine manner on microglia (Kuno et al, 2005;Takeuchi et al, 2006) and a paracrine manner on neurons; however, increased caspase-8 activity in the target neurons demonstrates involvement of neuronal TNF-␣ receptors (Feuerstein et al, 1998;Gorman et al, 1998). Our observation that microglia activated by the mGluRII agonist, DCG-IV, secreted TNF-␣ (but not nitric oxide), and that TNF-␣ was required for neuron killing, is consistent with earlier studies using the same stimulus (Taylor et al, 2002(Taylor et al, , 2005.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Kaushal¹,

Schlichter²

2008

J. Neurosci.

287

218

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After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor B (NF-B), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-␣ (TNF-␣), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4Ј-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2ЈR,3ЈR)-2-(2Ј3Ј-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-␣ (not nitric oxide) and mediated TNF-␣-dependent neurotoxicity through activation of NF-B (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNF␣ overproduction, and NF-B activation to reduce neuron death in the ischemic penumbra.

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Autocrine activation of microglia by tumor necrosis factor-α

Cited by 190 publications

References 42 publications

Tumor Necrosis Factor Receptor-1 is Essential for LPS-Induced Sensitization and Tolerance to Oxygen—Glucose Deprivation in Murine Neonatal Organotypic Hippocampal Slices

Tumor Necrosis Factor Receptor-1 is Essential for LPS-Induced Sensitization and Tolerance to Oxygen—Glucose Deprivation in Murine Neonatal Organotypic Hippocampal Slices

Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

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