Strongly compromised inflammatory response to brain injury in interleukin‐6‐deficient mice

Abstract

Injury to the central nervous system (CNS) elicits an inflammatory response involving activation of microglia, brain macrophages, and astrocytes, processes likely mediated by the release of proinflammatory cytokines. In order to determine the role of interleukin-6 (IL-6) during the inflammatory response in the brain following disruption of the blood-brain barrier (BBB), we examined the effects of a focal cryo injury to the fronto-parietal cortex in interleukin-6-deficient (IL-6-/-) and normal (IL-6+/+) mice. In IL-6+/+ mice, brain injury resulted in the appearance of brain macrophages and reactive astrocytes surrounding the lesion site. In addition, expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and metallothionein-I+II (MT-I+II) were increased in these cells, while the brain-specific MT-III was only moderately upregulated. In IL-6-/- mice, however, the response of brain macrophages and reactive astrocytes was markedly depressed and the number of NSE positive neurons was reduced. Brain damage-induced GM-CSF and MT-I+II expression were also markedly depressed compared to IL-6+/+ mice. In contrast, MT-III immunoreactivity was markedly increased in brain macrophages and astrocytes. In situ hybridization analysis indicates that MT-I+II but not MT-III immunoreactivity reflect changes in the messenger levels. The number of cell divisions was similar in IL-6+/+ and IL-6-/- mice. The present results demonstrate that IL-6 is crucial for the recruitment of myelo-monocytes and activation of glial cells following brain injury with disrupted BBB. Furthermore, our results suggest IL-6 is important for neuroprotection and the induction of GM-CSF and MT expression. The opposing effect of IL-6 on MT-I+II and MT-III levels in the damaged brain suggests MT isoform-specific functions.

The Role of Neuroinflammation in Traumatic Brain Injury

“…These clinical data support the conventional opinion of IL-6 being a mainly neuroreparative cytokine in the pathophysiology of head injury [102]. This notion is further supported by experimental studies on axotomy and cryogenic brain injury models, which provided evidence of strongly comprised inflammatory reactions in the brains of IL-6 gene-deficient mice [109,110]. Astrocyte-targeted overexpression of IL-6 in the intracranial compartment was previously reported to induce neurotoxicity by induction of a neurodegenerative inflammatory encephalopathy [111].…”

Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome

“…However, IL-6 over-expression has also been associated with neurodegeneration, astrogliosis, blood brain barrier (BBB) permeability, and increases in other pro-inflammatory cytokines including IL-1b and TNFa (Brett et al, 1995;Campbell et al, 1993;DiSanto et al, 1996;Penkowa et al, 1999). Collectively, these studies, along with our own data, suggest that IL-6 may serve as a biomarker of the overall CNS inflammatory burden, and a crucial determinant of clinical outcome following TBI.…”

“…Inflammation in the context of TBI can be viewed as a ''doubleedged sword'' that has benefits in supporting neuronal rescue, but also contributes to CNS damage, including astrogliosis (Penkowa et al, 1999;Swartz et al, 2001). Immediately following TBI, IL-6 upregulation during the acute inflammatory response can be beneficial to recovery in experimental studies (Penkowa et al, 2000), but sustained IL-6 production can have deleterious effects (Brett et al, 1995).…”

Gold ions bio-released from metallic gold particles reduce inflammation and apoptosis and increase the regenerative responses in focal brain injury

“…This model of traumatic brain injury was previously described in details (Penkowa and Moos 1995;Penkowa et al 1999Penkowa et al , 2000Penkowa et al , 2003. We have applied this freezelesion model for more than a decade producing very reliable (consistent and reproductive) results.…”

“…The primary antibodies were detected using biotinylated secondary antibodies (incubation for 30 min at room temperature) as previously described and listed in Penkowa et al (1999Penkowa et al ( , 2000Penkowa et al ( , 2003Penkowa et al ( , 2004Penkowa et al ( , 2006, followed by streptavidin-biotin-peroxidase complexing (StreptABComplex/ HRP, Dako, DK, code K377) and tyramide signal ampliWcation (TSA)-kit (NEN, Life Science Products, USA, code NEL700A), according to the manufacturer's recommendations. Finally, the immunoreactions were visualized using DAB as chromogen.…”