cFLIP is critical for oligodendrocyte protection from inflammation
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 ol...
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Veröffentlicht in: | Cell death and differentiation 2015-09, Vol.22 (9), p.1489-1501 |
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Zusammenfassung: | 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 (IFN
γ
) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNF
α
)-induced cytotoxicity. IFN
γ
protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-
κ
B activation. Although NF-
κ
B activation also occurred transiently in the absence of IFN
γ
and presence of TNF
α
, this activation was not sufficient to prevent induction of the TNF
α
-responsive cell death pathway. Genetic inhibition of NF-
κ
B translocation to the nucleus abrogated IFN
γ
-mediated protection and did not change the cell death induced by TNF
α
, suggesting that NF-
κ
B activation via IFN
γ
induces a different set of responses than activation of NF-
κ
B via TNF
α
. A promising candidate is the NF-
κ
B target cFLIP (cellular FLICE (FADD-like IL-1
β
-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFN
γ
-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNF
α
and short hairpin RNA knockdown of cFLIP-abrogated IFN
γ
-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 IFN
γ
-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNF
α
-induced cell death. |
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ISSN: | 1350-9047 1476-5403 |
DOI: | 10.1038/cdd.2014.237 |