Astrocyte-derived microparticles initiate a neuroinflammatory cycle due to carbon monoxide poisoning

Abstract

We hypothesized that carbon monoxide (CO) establishes an inflammatory cycle mediated by microparticles (MPs). Mice exposed to a CO protocol (1000 ​ppm for 40 ​min and then 3000 ​ppm for 20 ​min) that causes neuroinflammation exhibit NF-κB activation in astrocytes leading to generation of MPs expressing thrombospondin-1(TSP-1) that collect in deep cervical lymph nodes draining the brain glymphatic system. TSP-1 bearing MPs gain access to the blood stream where they activate neutrophils to generate a new family of MPs, and also stimulate endothelial cells as documented by leakage of intravenous 2000 ​kDa dextran. At the brain microvasculature, neutrophil and MPs sequestration, and myeloperoxidase activity result in elevations of the p65 subunit of NF-κB, serine 536 phosphorylated p65, CD36, and loss of astrocyte aquaporin-4 that persist for at least 7 days. Knock-out mice lacking the CD36 membrane receptor are resistant to all CO inflammatory changes. Events triggered by CO are recapitulated in naïve wild type mice injected with cervical node MPs from CO-exposed mice, but not control mice. All MPs-mediated events are inhibited with a NF-κB inhibitor, a myeloperoxidase inhibitor, or anti-TSP-1 antibodies. We conclude that astrocyte-derived MPs expressing TSP-1 establish a feed-forward neuroinflammatory cycle involving endothelial CD36-to-astrocyte NF-κB crosstalk. As there is currently no treatment for CO-induced neurological sequelae, these findings pose several possible sites for therapeutic interventions.

Hyperbaric oxygen should be used for carbon monoxide poisoning

“…Neurological sequelae appear up to 21 days after poisoning and are poorly correlated to COHb levels. Recent studies indicate that neuropathology evolves over days to weeks post‐exposure due to a cyclic inflammatory process initiated by astrocytes and exacerbated by circulating neutrophils 11 . Interleukin (IL)‐1β, IL‐6, TNFα and NF‐κB are elevated in the cerebral cortex and hippocampus in animal models 12–14 .…”

“…Recent studies indicate that neuropathology evolves over days to weeks post-exposure due to a cyclic inflammatory process initiated by astrocytes and exacerbated by circulating neutrophils. 11 Interleukin (IL)-1β, IL-6, TNFα and NF-κB are elevated in the cerebral cortex and hippocampus in animal models. [12][13][14] Patients with encephalopathy exhibit increases in IL-1β, IL-6, IL-10 and others in cerebrospinal fluid (CSF) and plasma.…”

Hyperbaric oxygen should not be used routinely for carbon monoxide poisoning

“…Fourth—and this is an especially important point—the pathophysiology of CO poisoning is more complex than generally appreciated. While it is widely appreciated that CO displaces oxygen from haemoglobin and shifts the oxygen–haemoglobin dissociation curve to the left, impairing peripheral oxygen delivery, it also generates reactive oxygen species, 3 inhibits cellular respiration by binding to mitochondrial haem and directly peroxidates brain lipids, leading to neuroinflammation 4 …”

“…While it is widely appreciated that CO displaces oxygen from haemoglobin and shifts the oxygenhaemoglobin dissociation curve to the left, impairing peripheral oxygen delivery, it also generates reactive oxygen species, 3 inhibits cellular respiration by binding to mitochondrial haem and directly peroxidates brain lipids, leading to neuroinflammation. 4 Clinicians who treat CO poisoning know that supplemental oxygen hastens the elimination of carboxyhaemoglobin and that HBO hastens it yet further. The elimination half-life of carboxyhaemoglobin while breathing room air averages about 6 h, falling to around 75 min when breathing 100% oxygen (normobaric oxygen, NBO) and about 22 min when breathing 100% oxygen at 3 atm.…”

Exploration of cerebral vasospasm from the perspective of microparticles

“…The current study focused on the effects of other types of BDMPs on neurons including changes in their morphology and synaptic plasticity ( Pistono et al, 2020 ). In addition, glial cell-derived MP may contribute to neuroinflammation ( Ruhela et al, 2021 ). The effect of BDMPs on vascular tone has not received enough attention and direct evidence is sparse.…”