Microglial TAK1 contributes to aging-related cerebrovascular dysfunction 3463

Description Objective Aging is frequently accompanied by cerebrovascular dysfunction, but the underlying immune mechanism remains largely unknown. Methods The morphology and function of cerebral arteries were assessed in young (3 months old) and old (24 months old) male C57 BL/6 mice. The roles of TAK1 and IL-18 in cerebrovascular dysfunction were examined using specific blocking antibodies and lenti-viruses in mice. Results We found a significant activation of microglia and microglial transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) in the brain stem of old mice. Depletion of microglia or pharmacological inhibition of TAK1 led to an alleviation of vascular dysfunction, including increased vessel wall thickness, collagen deposition, and endothelial dysfunction of the basilar artery. In contrast, microglia-specific activation of TAK1 induced cerebrovascular dysfunction in middle-aged mice. Moreover, TAK1 activation was found to enhance the production of IL-18, a pro-inflammatory cytokine. Overproduction of IL-18 resulted in basilar artery impairment, while blockade of the IL-18 receptor improved cerebrovascular function in old mice. Conclusion The findings indicate that microglial TAK1 plays an important role in aging-related cerebrovascular dysfunction. Blockade of TAK1 and IL-18 signaling might represent a promising strategy for the treatment of cerebrovascular aging. Funding Sources N.A. Topic Categories Neuroimmunology (NEUR)