Endothelial receptor CD36 engagement of microparticles triggers neuroinflammation and glymphatic dysfunction in CO...

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.