Abstract
Inflammation eliminates pathogenic infections while also threatening the integrity of the central nervous system. In this study, using in vivo and in vitro models of acute neuroinflammation, we investigated the mechanisms by which inflammation and astrocytes affect neuronal apoptosis. The in vitro model mimicked acute neuroinflammation by incubation in IFN-γ-containing media with primary cultured cerebellar granule neurons, with or without cultured astrocytes. This quickly induced neuronal apoptosis characterized by cleaved caspase-3 expression, Hoechst 33342 staining, and intercellular Ca2+ influx, whereas the presence of astrocytes significantly protected neurons from these effects. IFN-γ in the inflammation media also promoted astrocyte secretion of IL-6, essential for protection. The supernatants of rat peripheral blood mononuclear cells stimulated by lymphocyte mitogen lipopolysaccharide or concanavalin A were used as inflammation media to verify the results. The in vivo model involved a peripheral challenge with lipopolysaccharide, with or without recombinant IFN-γ, in C57BL/6 mice. This confirmed the in vitro results: anti-IFN-γ antibodies exacerbated the acute course of neuroinflammation and led to neurocyte apoptosis in vivo. The pro-inflammatory cytokine IFN-γ provided neuroprotection during acute neuroinflammation via induction of astrocyte-secreted IL-6. The findings provide novel insights into the mechanisms of neuroprotection by IFN-γ during acute neuroinflammation, and may impact therapies for inflammation-related central nervous system injury and disease.
Highlights
Pro-inflammatory cytokines, such as IL-1β, Tumor necrosis factor (TNF)-α, and IL-6, have multiple roles in both neurodegeneration and protection
The results showed that anti-IFN-γ antibody treatment delayed resolution of acute inflammation, and IFN-γ was responsible for neuroprotective IL-6 secretion by activated astrocytes
To determine how this acute inflammatory environment affects neurons and to investigate the role of the pro-inflammatory cytokine IFN-γ, we incubated primary cultured cerebella granule neurons (CGNs) in inflammation media derived from supernatants of Peripheral blood mononuclear cells (PBMC) of Wistar rats under either LPS or concanavalin A (ConA) stimulation [11]
Summary
Pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, have multiple roles in both neurodegeneration and protection. Research has shown that IFN-γ induces neuronal damage during chronic inflammation [11]; other reports have indicated a neuroprotective role for IFN-γ, associated with immunemediated mechanisms [12,13,14] These reports imply that inflammatory cytokines may mediate opposite effects based on the specific situation. LPS and ConA are mitogens that non- stimulate T and B cells, activation of which can quickly produce abundant proinflammatory cytokines, including IFN-γ and IL-6, as in the active immune response [11] In such an inflammatory environment, the activation of astrocytes via the release of additional cytokines into the buffer protects neurons while sustaining the local inflammatory environment for a certain period of time. Our data elucidated some of the mechanisms of the inflammatory environment and astrocytes with regard to neuronal apoptosis, which may provide a novel strategy to prevent neuronal damage during inflammatory CNS injury and disease
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