Neuronal IL-1R1 Signaling in Mild Closed Head Injury

ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following a traumatic brain injury (TBI), and substantial evidence suggests therapies targeting the interleukin-1 receptor (IL-1R1) pathway may control neuroinflammation. Recently identified neuron-specific IL-1R1 signaling, however, raises substantial concern about the overlooked neuroprotective functions of interleukin-1 (IL-1). Also, there is currently a lack of evidence demonstrating that IL-1 is directly detrimental to neuronal health. The neuroprotective functions of IL-1 have largely been ignored because of the well-defined detrimental role of IL-1 in inflammatory diseases. Neurons are the only cell in the body with multiple receptor pathways for recognizing IL-1, which all require IL-1R1 gene. Of note, the recently identified pathway IL1R1AcPb, which is highly expressed by neurons, has been shown to promote the survival of neurons. A lack of knowledge concerning the direct role of IL-1/IL-1R1 on neurons could undermine many potential neuroprotective approaches that target suppression of neuroinflammation as part of the mechanism-of-action. Our overarching hypothesis is that neuronal IL-1 signaling is inherently protective. Using two novel mouse models (IL-1R1-floxed and IL- 1R1-restore) that allow for inducible neuron-specific manipulation of IL-1R1, we will test in vivo the function of IL-1R1 following a mild TBI in the following specific aims (SA): SA1 Define the contribution 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 phenotypic 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.