Zuha Imtiyaz

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.

Elevated glymphatic flow, glial cell activation, increased circulating microparticles (MPs), and neutrophil activation due to decompression have been well documented in animal models. This report shows that filamentous (F)-actin expressing MPs produced postdecompression interact with endothelial CD36 driving a feed-forward neuroinflammatory cycle and inducing vascular injury.

The mechanism for neurological deficits from carbon monoxide (CO) poisoning is unclear. In a series of 150 patients with CO poisoning, we found marked elevations of blood-borne inflammatory filamentous (F-) actin–coated microparticles (MPs), neutrophil activation, and a 90% reduction in the normal level of plasma gelsolin (pGSN), a protein capable of lysing F-actin–coated MPs. This led to studies in a murine model where the same events occur and cause neuroinflammation with cognitive dysfunction. All events are recapitulated when F-actin MPs are injected intravenously, which establishes a blood-to-brain-to-blood inflammatory cycle that persists for weeks. All changes, including cognitive dysfunction, can be abrogated by an injection of human recombinant pGSN within 2 weeks after CO poisoning. These findings demonstrate that CO-induced neurological injury has an inflammatory etiology. Because of MP-mediated communications between the brain and systemic circulation, CO-induced cognitive deficits may be reversible with a pharmaceutical intervention.