Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration

Shaftel, Solomon S.; Carlson, Thaddeus; Olschowka, John A.; Kyrkanides, Stephanos; Matousek, Sarah B.; O’Banion, M. Kerry

doi:10.1523/jneurosci.1418-07.2007

Cited by 226 publications

(248 citation statements)

References 53 publications

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“…Controls also consisted of intracranial injections as above into non-transgenic (WT) littermates. To confirm that the induction of inflammation is specific to the site of transgene activation, we labeled sections with CD45 and found, consistent with previous reports, 45 robust leukocyte infiltration into the CNS of Figure 3f). Data are plotted as mean ± S.E.M.…”

Section: Resultssupporting

confidence: 85%

“…While the number of TUNEL + oligodendrocytes seems small in relation to the decrease in FluoroMyelin staining intensity, this may be owing to the rapid pace at which apoptotic oligodendrocytes are cleared from the white matter, which may be accelerated during neuroinflammation and macrophage infiltration. 45 The possibility of IFNγ-induced cFLIP upregulation acting as a protective pathway seems consistent with studies, reporting that elimination of IFNγ expression increases EAE severity, 55,56 and that its expression can protect against disease onset, 57 oligodendrocyte death and demyelination induced by cuprizone. 58 However, the protective effect might depend on the concentration, timing and/or source of IFNγ, as there are also studies showing that administration of IFNγ to multiple sclerosis patients, or in animals with EAE, can worsen inflammation and clinical symptoms.…”

Section: Discussionsupporting

confidence: 75%

“…Exposure to Cre recombinase induces IL-1β expression, reaching peak inflammation at 14 days. [45][46][47] We further confirmed that intracranial injection of Cre recombinase-expressing lentivirus caused upregulation of a number of inflammatory markers, including IFNγ and TNFα (Figure 7d). …”

Section: Resultssupporting

confidence: 64%

“…This model was uniquely well suited for our studies, as IL-1β expression leads to robust leukocyte recruitment to the CNS, astrocyte activation and induction of pro-inflammatory cytokines but no oligodendrocyte toxicity. 45,47 Although the reasons for the absence of toxicity were initially not clear, our analyses showed a robust upregulation of cFLIP expression in IL-1β XAT mice, thereby raising the question of whether this might be protective. Indeed, cFLIP knockdown with shRNA led to a significant increase in TUNEL + oligodendroyctes in addition to a decrease in global myelin staining intensity.…”

Section: Discussionmentioning

confidence: 82%

“…IL-1β XAT mice show no overt oligodendrocyte death despite significant leukocyte infiltration into the CNS, [45][46][47] suggesting Figure 4 PKR activation is required for IFNγ-mediated oligodendrocyte protection. (a) Whole-cell lysates were obtained from oligodendrocytes treated as indicated for 72 h and probed by western blotting for PKR, phospho-eIF2α, eIF2α, phospho-PERK, PERK and β-tubulin.…”

Section: Resultsmentioning

confidence: 99%

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cFLIP is critical for oligodendrocyte protection from inflammation

et al. 2015

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Neuroinflammation associated with degenerative central nervous system disease and injury frequently results in oligodendrocyte death. While promoting oligodendrocyte viability is a major therapeutic goal, little is known about protective signaling strategies. We report that in highly purified rat oligodendrocytes, interferon gamma (IFNγ) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNFα)-induced cytotoxicity. IFNγ protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-κB activation. Although NF-κB activation also occurred transiently in the absence of IFNγ and presence of TNFα, this activation was not sufficient to prevent induction of the TNFα-responsive cell death pathway. Genetic inhibition of NF-κB translocation to the nucleus abrogated IFNγ-mediated protection and did not change the cell death induced by TNFα, suggesting that NF-κB activation via IFNγ induces a different set of responses than activation of NF-κB via TNFα. A promising candidate is the NF-κB target cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFNγ-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNFα and short hairpin RNA knockdown of cFLIP-abrogated IFNγ -mediated protection. To determine the relevance of our in vitro finding to the more complex in vivo situation, we determined the impact on oligodendrocyte death of regional cFLIP loss of function in a murine model of neuroinflammation. Our data show that downregulation of cFLIP during inflammation leads to death of oligodendrocytes and decrease of myelin in vivo. Taken together, we show that IFNγ-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNFα-induced cell death.

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Section: Resultssupporting

confidence: 85%

Section: Discussionsupporting

confidence: 75%

Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

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cFLIP is critical for oligodendrocyte protection from inflammation

et al. 2015

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Neuroinflammation in Alzheimer's, Parkinson's and Huntington's Diseases

Sastre

Katsouri

Birch

et al. 2014

Neuroinflammation and CNS Disorders

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The Neuroinflammatory Response to Nanopatterning Parallel Grooves into the Surface Structure of Intracortical Microelectrodes

Ereifej

Smith

Meade

et al. 2017

Adv Funct Materials

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The smooth surface structure of intracortical microelectrodes implanted within the nanometer‐scale architecture of brain tissue may contribute to the foreign body response. Here, the neuroinflammatory response to nanopatterning surface grooves etched directly on nonfunctional Michigan‐style microelectrodes is explored. Rats implanted with nanopatterned silicon microelectrodes are compared to smooth control implants to observe the effects the grooves have on neuroinflammation. Histology and real‐time PCR at 2 and 4 weeks postimplantation quantify glial cell reactivity and activation, inflammation, oxidative stress, and neuronal survival. Histological observations of glial cells and blood–brain barrier permeability do not show appreciable differences between the nanopatterned and control implants. However, silicon microelectrodes with nanopatterned grooves have more high mobility group box 1 (HMGB1) gene expression at 2 weeks and less nitric oxide synthase (NOS2) gene expression at 4 weeks compared to control surfaces. Control samples have increased NOS2, HMGB1, and tumor necrosis factor gene expression from 2 to 4 weeks, while nanopatterned implants have significant decrease in CD14 gene expression from 2 to 4 weeks. Collectively the results indicate that etching nanopatterned grooves do not reduce histological markers of neuroinflammation compared to control implants, but gene expression results encourage further investigation.

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Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration

Abstract: The proinflammatory cytokine interleukin-1␤ (IL-1␤

Cited by 226 publications

References 53 publications

cFLIP is critical for oligodendrocyte protection from inflammation

cFLIP is critical for oligodendrocyte protection from inflammation

Neuroinflammation in Alzheimer's, Parkinson's and Huntington's Diseases

The Neuroinflammatory Response to Nanopatterning Parallel Grooves into the Surface Structure of Intracortical Microelectrodes

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