Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

Abstract

The relevance of astrogliosis remains controversial, especially with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. This dichotomy can be resolved if the mediators of astrogliosis are identified. We have measured the levels of transcripts encoding inflammatory cytokines in injury systems in which the presence or absence of astrogliosis could be produced selectively. A stab injury to the adult mouse brain using a piece of nitrocellulose (NC) membrane elicited a prompt and marked increase in levels of transcripts for interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α, which are considered to be microglia/macrophage cytokines. The elevations preceded, or occurred concomitantly with, the rise in glial fibrillary acidic protein mRNA, an early manifestation of astrogliosis. In neonatal mice, IL-1 and TNF-α mRNA were elevated to a greater extent by an NC-implant injury, which produced astrogliosis, than after an NC-stab, with minimal astrogliosis. We determined whether endogenous interferon (IFN)-γ could be responsible for the observed increases in IL-1 and TNF-α, because IFN-γ is a potent microglia/macrophage activator, and because its exogenous administration to rodents enhanced astrogliosis after adult or neonatal insults. A lack of requirement for endogenous IFN-γ was demonstrated by three lines of evidence. First, no increase in IFN-γ transcripts could be found at injury. Second, the administration of a neutralizing antibody to IFN-γ did not attenuate astrogliosis. Third, in IFN-γ knockout adult mice, astrogliosis and increases in levels of IL-1α and TNF-α were induced rapidly by injury. The marked elevation of inflammatory cytokines is discussed in the context of astrogliosis and general CNS recovery.

Central Nervous System-Initiated Inflammation and Neurotrophism in Trauma: IL-1β Is Required for the Production of Ciliary Neurotrophic Factor

“…From the investigations of numerous groups, it has become evident that an increase in the levels of proinflammatory cytokines is a normal and early feature of the CNS response to trauma (1)(2)(3). In particular, we have shown that IL-1 and TNF-␣ become significantly elevated within the CNS parenchyma by 3 h after a brain stab wound injury, and are localized to the lesion site (4).…”

Impaired Wound Healing after Cerebral Hypoxia—Ischemia in the Diabetic Mouse

“…In a rat model of transient focal ischemia expression of TNFa and IL-1b mRNA was detected as early 1 h and peaked at 3 and 6 h, respectively (Wang et al, 1995). The induction of TNFa and IL-1b have been shown to be induced early in other brain injuries, for example, in a stabwound injury model in adult mouse brain, elevation of IL-1b and TNFa mRNA were observed at 6 to 12 h after the injury (Rostworowski et al, 1997).…”

Microglia at brain stab wounds express connexin 43 andin vitroform functional gap junctions after treatment with interferon-γ and tumor necrosis factor-α

“…Moreover, elevation of INF-␥ has been found in the brain of animals with autoimmune disorders such as experimental allergic encephalomyelitis (42,43), suggesting that under these conditions microglia might communicate to each other via Cx43 gap junctions induced by TNF-␣ plus INF-␥. On the other hand, after acute trauma the brain levels of INF-␥ mRNA remain unchanged, and in INF-␥ (Ϫ͞Ϫ) mice astrogliosis is still observed (44); thus, the inflammatory response after brain trauma may be mediated by a different set of cytokines. The fact that LPS or TNF-␣ plus INF-␥ did not induce dye coupling in every cultured microglial cell could be due to the known heterogeneity of microglia (45), the need for additional inflammatory mediators, and failure to use an appropriate concentration of the cytokines tested.…”