The Role Of Microglial Tak1 In Prolonged Obesity-related Cerebrovascular Dysfunction

Objective:To investigate the role of microglial TGF-? activated kinase 1(Tak1)in obesity-related cerebrovascular dysfunction.Methods:We established a cohort of diet-induced obesity mice,and then assessed the activity of Tak1 as well as the morphology and function of basilar artery(BA).The approaches,including pharmalogical inhibition,microglia-specifc knockout of Tak1,or lentivirus-mediated expression constitutively active Tak1,were employed in the current study.In addtion,the expression of cytokines and chemokines were profliled using RNA extracted from the brain stem of chow-and HFD-fed mice.Moreover,we investigated the role of Tak1 in the regulation of the production of IL-18 using both the BV2 microglial cell line and the mouse model.We then treated the rat aortic endothelial cells with IL-18,and then assessd the activity of endothelial nitric oxide synthase(e NOS).We injected the antibody against Il-18 receptor ? into the fourth ventricle of prolonged diet-induced obesity and control mice,and then assessed the morphology and function of the BA.We generated the triansient middle cerebral artery occlusion(MCAO)mouse model using prolonged HFD-fed Tak1 knockout and littermate control mice,and then assessed the neurological score and infarct volume.Results:There were microgliosis and Tak1 activation in the microglia of brain stem in the prolonged diet-indcued obesity mice.Pharmacological inhibition or genetic knockout of Tak1 in brain stem microglia improved BA dysfunction in the prolonged obesity mice.Moreover,activation of Tak1 in the microglia of brain stem significantly impaired BA function in chow-fed C57 BL/6 mice.Prolonged obesity led to the overexpression of IL-18 in the brain stem.Importantly,Tak1 promoted the production of IL-18 in microglial cells.Moreover,IL-18 treatment inhibited the activity of e NOS in RAECs.Blockade of IL-18 receptor ? could remarkably improve cerebrovascular dysfunction in prolonged obesity mice.Lastly,microglia-specific deletion of Tak1 could greatly reduce the infarct volume and improve the prognosis after ischemic stroke in the proloned diet-induced obesity mice.Conclusions:Microglial Tak1 plays a important role in prolonged obesity-related cerebrovascular dysfunction.Targeting Tak1 might be relevant for the prevention or treatment of this pathology.