Abstract
BackgroundInterleukin 1 (IL-1) is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD), for example, pre-clinical and clinical studies have implicated IL-1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signaling in vivo would correlate with increased severity of AD-relevant neuroinflammation and neuronal damage.MethodsTo test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Aβ)-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO) and wild-type (WT) littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Aβ1–42. This model mimics many features of AD, including robust neuroinflammation, Aβ plaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Aβ for 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed.ResultsIL1raKO mice showed increased vulnerability to Aβ-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Aβ-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia.ConclusionOur data are consistent with the neuroinflammation hypothesis whereby increased IL-1 signaling in AD enhances glia activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae.
Highlights
Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease
Enhanced microglial responses in Aβ-infused IL-1 receptor antagonist Knock-Out (IL1raKO) mice Based on the high mortality seen in Aβ-infused IL1raKO mice, the infusion experiment was repeated with additional mice to allow survival of enough KO mice for subsequent analyses
Measurement of microglia activation endpoints (Fig 2) revealed no significant differences in the basal levels of the pro-inflammatory cytokines IL-1β (Fig 2A) and TNFα (Fig 2B) in vehicle-infused IL1raKO and WT mice
Summary
Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease. classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. Increased levels of inflammatory and oxidative stress molecules produced by chronically activated glia can lead to neuron damage or death, which can induce further glial activation, leading to a self-propagating, detrimental cycle of neuroinflammation and neurodegeneration [3]. A large body of evidence [4,5,6,7,8] suggests that targeting this glianeuron cycle represents an attractive potential strategy for development of new therapeutic approaches to AD that would alter disease progression To this end, a more detailed understanding of the proteins, pathways, and inflammatory responses involved in neuroinflammation relevant to AD progression is critical. Multiple studies examining IL-1 genetics have shown that polymorphisms in the IL-1gnd IL-1 receptor genes increase the risk of AD by as much as three times in a homozygous carrier [17,16]
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