Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury

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. Despite the promise, there have been limited attempts to move anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. While the reason for the lack of progress on this promising target is likely multifactorial, we hold that a limitation in our understanding of the mechanistic underpinnings of IL-1 signaling after a TBI, particularly after a mild TBI, is impeding the translational efforts of targeting neuroinflammation for TBI neuroprotection. It is well-recognized that clinical picture of TBI is a spectrum of different primary injury mechanisms (e.g. contusions, hematomas, diffuse axonal injury) and injury severities (i.e. mild, moderate, severe), and that it is necessary to understand the secondary injury mechanism as they relate to primary injury mechanisms and injury severities. Over 75% of TBIs are classified as mild. The current knowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury. Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling, and our model of mild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge by testing the role of IL-1R1 in a mild TBI, and for the first time, define a cellular mechanism for how IL-1R1 is excreting pathological effects following a mild TBI. Importantly our exciting preliminary data has uncovered a critical role for the brain endothelium in regulating neuroinflammation, which is dependent on IL-1R1. Our exciting preliminary results have led us to propose the overall hypothesis: Global loss of IL-1R1 will have a key role in reducing the pathophysiology of experimental mild traumatic brain injury (TBI). The actions of IL-1R1 following a mild TBI will require involvement of endothelial cells. The mechanism linking the TBI induced pathophysiology will include IL-1R1 dependent neuroinflammation and vascular dysfunction. To investigate the mechanisms and neuroprotective potential of IL-1R1 in experimental mild TBI, we propose the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mild TBI, and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our results will fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotection after a mild TBI. PROJECT NARRATIVE Emerging evidence suggests that selective modulation of neuroinflammation is a promising avenue for improving patient outcomes following a traumatic brain injury (TBI). We have recently demonstrated that interleukin-1 receptor (IL-1R1) pathway may control neuroinflammation at the level of the blood vessel, providing evidence of an underappreciated mechanism of how the brain becomes inflamed after a TBI. In this project, we propose to determine the role of endothelial IL-1R1 after experimental mild TBI with the goal of providing the knowledge necessary to enable the development of selective modulators of neuroinflammation for TBI.