Blockade Of Both Il-1A And Il-1B Are Necessary For Maximal Anti-Inflammatoryand Cognitive Benefit Following TBI

IL-1 is a central regulator of the immune response to acute brain injury. IL-1α and IL-1β are the best-characterized cytokines of this family and signal through IL-1 receptor (IL-1RI). An understanding of the contribution of individual IL-1 pathway molecules following TBI is lacking and is of vital importance in developing potential anti-IL-1 therapies. We use lateral fluid percussion injury adapted to mice targeting moderate-severe TBI. C57BL6J and global IL-1 KO mice (on C57BL6J background) were used. Gene expression was evaluated by qPCR. Barnes maze testing was used to evaluate cognitive function 2 weeks post-TBI. FPI resulted in increased inflammatory cytokine expression (IL-1α, IL-1β, TNF and IL-6) in both focal (left parietal cortex, hippocampus) and remote regions (brainstem, cerebellum). At 6 hours, IL-1RI ablation decreased the spread of IL-1β and IL-6 expression to remote regions (brainstem, cerebellum). At 24hrs, IL-1RI ablation improved resolution of IL-1β and IL-6 in both focal (parietal cortex) and remote (brainstem) regions. Compared to WT littermates, IL-1RI KO mice performed better in the Barnes maze probe trial whereas IL-1α and IL-1β KO mice showed no significant improvement. Conclusions: FPI results in a diffuse inflammatory response with increased expression of pro-inflammatory cytokines at the injury epicenter, and in areas remote from impact. Combined, but not individual IL-1α and IL-1β blockade, prevented spread and hastened resolution of inflammatory cytokine expression. Furthermore, ablation of IL-1α or IL-1β alone was insufficient for cognitive protection following TBI, whereas combined blockade via IL-1RI ablation did result in cognitive rescue. Pharmacologic IL-1RI blockade appears to be a superior therapeutic strategy over individual IL-1 molecule blockade following TBI.