The domino effect in inhaled carbon black nanoparticles triggers blood brain barrier disruption via altering circulatory inflammation

The bloodbrain barrier (BBB) impedes the influx of most compounds from the blood to the brain, and its integrity is a hallmark of nervous system health. Nanoparticles can cross the BBB through transcytosis, direct BBB impairment, reverse neuronal transport, and others. However, it is still ambiguous how the inhaled nanoparticles affect the BBB integrity. Herein, we evaluated the BBB disruption after carbon black nanoparticles (CBNPs) inhalation exposure and proposed a domino effect hypothesis to explain the extrapulmonary toxicity of inhaled nanoparticles. Mechanistically, inhaled CBNPs were internalized by alveolar macrophages and initiated the inflammatory storm in the pulmonary, resulting in the subsequent circulatory inflammation in the internal systemic environment and damage to the cerebrovascular tight junction with zonula occludens-1 (ZO-1) reduction. Moreover, an ex vivo biosensor assay elucidated that Wnt/β-catenin signaling was closely associated with cerebrovascular endothelial cell impairment. Furthermore, the reversal of BBB breakdown with intraperitoneal injection of dexamethasone supported that pulmonary and circulatory inflammation played a significant role in the domino effect of inhaled CBNPs. Therefore, this study demonstrates the mechanism of extrapulmonary toxicity of inhaled CBNPs and provides potential early intervention targets for the nervous system injury.