Abstract:
Accumulating evidence over the past 20 years has indicated that the brain has an endogenous immune system, mediated at the local level predominantly by microglial cells. The primary role of an inflammatory response is to protect the host against a foreign stimulus, remove damaged cells and to initiate repair and regeneration of damaged tissue. However, it has become increasingly evident that this inflammatory response, in addition to its role in host defence and repair, can exert detrimental effects in the central nervous system (CNS). Neuroinflammation, as this response is now commonly known, has been implicated in the pathogenesis of many neurodegenerative diseases. Microglia, the resident macrophage of the brain, play a central role in sustaining this inflammatory response through the release of proinflammatory and potentially cytotoxic mediators. Hypothermia is neuroprotective, and these properties are thought to be mediated, in part, by the suppression of microglial activation.
The BV-2 microglial cell line was used to investigate the mechanisms involved in the activation and inhibition of microglia. Lipopolysaccharide (LPS)-induced activation of BV-2 cells led to the up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, the release of inflammatory mediators such as nitric oxide (NO), prostaglandin (PG)-E2, interleukin (IL)-6 and tumour necrosis factor (TNF)-α, and a change to a phagocytic phenotype. This response was mediated by the initiation of signal transduction pathways that culminated in transcription and translation of the inflammatory genes. Hypothermia (33°C) caused complete suppression of iNOS and NO whilst displaying little or no effect on IL-6 and TNF-α respectively. In contrast, LPS-induced COX-2 expression and PGE2 release was super-induced in response to hypothermia. A co-culture model of neuroinflammation was developed to investigate microglial-neuronal interactions. LPS/interferon (IFN)-γ activated BV-2 cells required direct contact with SK-N-SH neuroblastoma cells to elicit a cytotoxic phenotype. Hypothermia and the selective iNOS inhibitor S-methylisothiourea (S-MT) protected against this BV-2-induced SK-N-SH cell death, strongly implicating NO as the major candidate molecule in microglial-induced neuronal cell death.
Thus, microglial activation sustains the chronic inflammatory response in the CNS and in doing so contributes to further neuronal death. Inhibition of the detrimental facets of microglial activation may provide some protection against neurodegeneration.