Inflammation in the brain is now recognised as a major contributor in diverse CNS diseases. Amongst the inflammatory molecules, the cytokine interleukin-1 (IL-1) has been identified as a key mediator of neurodegeneration. IL-1 expression is induced rapidly in clinical and experimentally induced neurodegeneration, largely by glia. Administration of IL-1 exacerbates neuronal injury in rodents and, most importantly, inhibition of the expression, release or actions of endogenous IL-1 markedly reduces experimentally induced ischaemic, traumatic and excitotoxic brain injury. Understanding the mechanisms underlying the expression, release and actions of IL-1 is therefore of major scientific and clinical relevance.
Expression of IL-1 in the brain can be induced by many toxic insults, and is specifically increased in response to hypoxia, excessive neuronal activation and bacterial products. Release and activation of both forms of IL-1 (α and β) can be induced by activation of purinergic (P2X7) receptors in microglia in response to extracellular ATP and possibly other stimuli. IL-1β has no leader sequence so its mechanism of release is not known, but depends on release of intracellular calcium stores and cleavage by caspase 1. IL-1 is believed to act via a single receptor (IL-1R1) though our data suggest the presence of additional signalling receptors. IL-1’s mechanisms of action on neurodegeneration are largely unknown and probably multiple. IL-1 can protect neurones in vitro from excitotoxic insults, but induces the release of neurotoxins from glia. We have identified specific sites of action of IL-1 in the brain where it can induce or exacerbate extensive neuronal loss at distant sites in the brain, possibly due to enhancement of seizures. It may also influence neuronal susceptibility or death through its many physiological and pathophysiological actions, e.g. on body temperature, bloodÐbrain barrier integrity, extracellular matrix, neurotoxin invasion of immune cells into the CNS, cerebral oedema and synaptic plasticity.
The endogenous inhibitor of IL-1, IL-1 receptor antagonist (IL-1ra), appears to act as a functional inhibitor of neurodegeneration, and is a potential clinical treatment for stroke, brain injury and related disease.
This work was supported by MRC, BBSRC, EU and Syngenta plc.
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