NLRP3 Deficiency Ameliorates Neurovascular Damage in Experimental Ischemic Stroke
Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3 NOX2 or wild type (WT) mice. By magnetic resonance imaging (MRI) Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3 mediated interleukin 1b (IL 1b) release as evidenced by increased brain microvessel endothelial cell permeability and microglia mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2 mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3 mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
Journal of cerebral blood flow and metabolism official journal of the International Society of Cerebral Blood Flow and Metabolism