Interleukin-1 Receptor-1 Signaling Mediates Neuroinflammation, Neuronal Injury, and Cognitive Decline after Diffuse Traumatic Brain Injury

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, the TBI increased gliosis and the accumulation of leukocytes in the cortex were independent of IL-1R1.

IL1R1KO reduced the TBI associated increases in Il1b, Tnfa, and Irf7 mRNA in the hippocampus and cortex. Moreover, TBI reduced fear memory (cued) 7 dpi and increased NfL in the plasma. Both deficits were attenuated by IL1R1KO.

IL1R1 tdTomato reporter mice confirmed that IL1R1 was expressed in the DG 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% were 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.