Abstract T MP13: Tak1 Knockdown In Myeloid Lineage Protects Against Transient Focal Cerebral Ischemia In Mice

Abstract

Introduction: Stroke is 4 th cause of death and one of the leading causes of disability in United States. Transforming growth factor β activated kinase-1 (TAK1) is a major contributor in the progression of injury post stroke. Pharmacological inhibition of TAK1 is neuroprotective after stroke, but the cell type responsible for these effects is unknown. Myeloid cells play a key role in inflammation after stroke and selective deletion of TAK1 in myeloid cells reduced neuro-inflammation in models of multiple sclerosis. Therefore, we hypothesized that the detrimental effects of TAK1 activation after ischemic injury were mediated by myeloid-specific activation of TAK1. Methods: Young male ovary-intact and ovariectomized female [litter mates TAK fl/fl and TAK fl/fl LysM cre (mTAK-/-)], (8-12 weeks) were randomly divided into sham and stroke group and subjected to 90 minutes of right middle artery occlusion. Neurobehavioral assessments were performed after 24 hours and brains were taken for analysis. Results: In sham males, there was a significant increase in the percentage of circulating macrophages and neutrophils in mTAK-/- (62.48 ± 2.43 and 33.33 ± 3.01 respectively) compared to TAK fl/fl (35.38 ± 3.09 and 17.04 ± 3.26) (p<0.05) mice. After stroke, a significant decrease in macrophages and neutrophils was observed in mTAK-/- (22.60 ± 1.23 and 17.57 ± 2.60, respectively) compared to TAK fl/fl (72.90 ± 4.63 and 57.78 ± 5.9, respectively) (p<0.05). There was a significant improvement in neurological deficit score (NDS) in mTAK-/- (1.9 ± 0.4) compared to WT littermates (3 ± 0.7) (p<0.05). An increase in total TAK1 expression was seen in mTAK-/- mice after stroke but there was no difference in levels of phosphorylated TAK1 (p<0.05). In females, there was a significant improvement in the NDS and corner test in ovx mTAK-/-females (2.2 ± 0.4 and 0.7 ± 0.1) as compared to ovx TAK fl/fl females (3.0 ± 0.6and 0.9 ± 0.2) (p<0.05) respectively. Ovary intact mTAK-/- and TAK fl/fl females had similar infarct suggesting a role for estrogen in TAK signaling or post stroke inflammation. Conclusion: TAK1 deletion in myeloid cells leads to neuroprotection against ischemic injury. Further studies will be performed to determine the contribution of different cell types in the TAK1 signaling.