Interleukin-1 receptor-1 signaling mediates neuroinflammation, neuronal injury, and cognitive decline after diffuse traumatic brain injury.

Traumatic brain injury (TBI) increases the risk of developing neuropsychiatric illness and cognitive impairment. Previous work indicates that inflammatory pathways associated with interleukin (IL)-1 and interferon signaling persist in the brain chronically after TBI. Several cell types in the brain express the interleukin-1 receptor-1 (IL-1R1) including endothelia, astrocytes, and neurons. Therefore, the purpose of this study was to determine if IL-1R1-mediated signaling after TBI promotes neuroinflammation and disrupts neuronal homeostasis and cognition. Here, male and female wild-type and global IL-1R1 knock-out (KO) mice were used. Mice were subjected to a diffuse TBI induced by midline fluid percussion injury and several parameters were assessed 3, 7, and 30 days post injury (dpi). At 3 dpi, TBI increased gliosis, cortical inflammation, and the accumulation of leukocytes in the cortex. TBI-associated increase in leukocytes in the brain and neurofilament light chain (NfL) in the plasma 3 dpi were reduced by IL1R1KO. At 7 dpi, TBI increased gliosis in the cortex and hippocampus that was independent of IL-1R1. IL1R1KO reduced the TBI associated increases in Il1b, Tnfa, and Irf7 mRNA in the hippocampus and cortex. Moreover, TBI reduced cued fear memory 7 dpi and increased NfL in the plasma. Both deficits were attenuated by IL1R1KO. IL-1R1 tdTomato reporter mice confirmed that IL-1R1 was expressed in the dentate gyrus and increased by TBI 7 dpi. Next, snRNA-seq studies demonstrated a robust influence of TBI on RNA profiles in the dentate gyrus (DG) and CA1 of the hippocampus 7 dpi. The CA1 and DG had 2572 and 1012 differentially expressed genes (DEGs) influenced by TBI, respectively. Of these DEGs, the majority were decreased after TBI with 73 and 96% prevented in the CA1 and DG by IL1R1KO. These DEGs were associated with pathways for learning and memory, T-cell signaling, and synapse organization and maintenance. Furthermore, TBI-associated deficits in fear conditioning 30 dpi was attenuated in IL1R1KO mice. Consistent with this neuronal dysfunction in the hippocampus, there was IL-1R1-dependent decreased neuronal activation (pCREB) 30 dpi. Overall, these data indicate that IL-1R1 signaling after TBI mediated neuronal deficits associated with impaired cognition.