Neuronal IL-1R1 Signaling in Mild Closed Head Injury

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ABSTRACT The cytokine interleukin-1 (IL-1) is well known to mediate detrimental inflammatory processes in peripheral tissues. IL-1 is elevated in age and in neurodegenerative disease. As a result, IL-1 has become a major focus of anti-inflammatory strategies to treat neuroinflammation following acute injury and in chronic neurodegenerative disease. Surprisingly, there is scant evidence that neurons are damaged through the direct actions of IL-1. To the contrary, a neuron-specific “non-canonical” IL-1 receptor (IL-1R1) pathway that promotes, rather than erodes, neuronal viability has been identified. Despite this paradigm-shifting observation, the non-canonical pathway has received little attention. Much remains unknown about how neuronal IL-1R1 signaling contributes to the brain's inflammatory milieu, synaptic physiology, and cognitive function, and recover from injury and progression of neurodegeneration. This knowledge gap could undermine potential neuroprotective approaches that target suppression of IL-1 as part of the mechanism-of-action. To address this knowledge gap, we will use novel mouse models exhibiting neuron-specific modulation of IL-1 signaling (i.e., IL-1R1-floxed mice to look at neuron-specific knockdown and IL-1R1-restore mice to look at the neuron-specific expression of IL-1R1). Our overarching hypothesis is that neuronal IL-1R1 signaling is inherently protective. We will test this hypothesis in the following Specific Aims: SA1 Define the role of the neuronal IL-1R1 pathway in the inflammatory response to a CHI in mice. SA2 Define the neuronal IL-1R1 pathway in homeostatic synaptic plasticity after a CHI in mice. SA3 Determine the temporal role of neuronal IL-1R1 in the cognitive recovery following a CHI. If our hypothesis is affirmed, we will provide knowledge of a new neuroprotective approach and enable the development of new formulations of existing anti-inflammatory interventions that preserve the neuroprotective functions of IL-1. The development of novel IL-1R1 therapies would include agents that only suppress the inflammatory IL-1R1 pathway or only activate the neuroprotective IL-1R1 pathway.