cFLIP is critical for oligodendrocyte protection from inflammation

摘要

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 gamma) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNF alpha)-induced cytotoxicity. IFN gamma protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-kappa B activation. Although NF-kappa B activation also occurred transiently in the absence of IFN gamma and presence of TNF alpha, this activation was not sufficient to prevent induction of the TNF alpha-responsive cell death pathway. Genetic inhibition of NF-kappa B translocation to the nucleus abrogated IFN gamma-mediated protection and did not change the cell death induced by TNF alpha, suggesting that NF-kappa B activation via IFN gamma induces a different set of responses than activation of NF-kappa B via TNF alpha. A promising candidate is the NF-kappa B target cFLIP (cellular FLICE (FADD-like IL-1 alpha-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFN gamma-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNF alpha and short hairpin RNA knockdown of cFLIP-abrogated IFN gamma-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 gamma-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNF alpha-induced cell death.