一酸化炭素中毒における内皮受容体CD36エンゲージメントを介したミクロ粒子による神経炎症およびグリソン機能障害の誘発

Patients suffering carbon monoxide (CO) poisoning exhibit elevations of ∼1-μm diameter blood-borne microparticles that murine studies have demonstrated to be responsible for a weeks-long cycle of neuroinflammation leading to functional neurological deficits. We hypothesized that an early event in the cycle is enhanced glymphatic flow to release brain-derived MPs, and that the adherence of circulating MPs to the central nervous system vasculature occurs via endothelial CD36 to cause neutrophil sequestration, which disrupts the blood-brain barrier. Results demonstrate that endothelial CD36 engagement of microparticles is required for pathological events, including neutrophil sequestration, leading to a 2.5 ± 0.6-fold increased vasculature leakage of 6 MDa dextran and induction of neuroinflammatory proteins. These changes increase glymphatic flow by 95 ± 26% based on magnetic resonance imaging and fluorescent tracer uptake, resulting in the release of brain-derived microparticles capable of activating neutrophils that complete a cycle of progressive neuroinflammation. The cyclic cascade of events, shown to persist for 3 wk, failed to occur in CD36 knock-out mice and those conditionally deficient in endothelial CD36 (CD36^flox/flox; Tie2-Cre+). We conclude that endothelial CD36 engagement of circulating microparticles precedes and is required for neutrophil adherence to perpetuate the neuroinflammatory cycle involving brain-derived and blood-borne microparticles.NEW & NOTEWORTHY CO-induced neuroinflammation requires endothelial CD36 engagement of circulating microparticles that trigger neutrophil vascular adherence, neuroinflammation, and a transient elevation of glymphatic flow, establishing a self-perpetuating neuroinflammatory cycle.