A novel target to reduce microglial inflammation and neuronal damage after deep hypothermic circulatory arrest

Neuroinflammation acts as a contributor to neurologic deficits after deep hypothermic circulatory arrest. However, the molecular mechanism remains unclear. This study postulates that cold-inducible RNA-binding protein can promote deep hypothermic circulatory arrest-induced neuroinflammation.

Enhanced cold-inducible RNA-binding protein in microglia aggravates neuronal injury by promoting the release of proinflammatory cytokines, which might be mediated through Brd2-NF-κB signals during deep hypothermic circulatory arrest.

Rats were randomly assigned into 3 groups (n = 5, each group): sham group, deep hypothermic circulatory arrest group, and deep hypothermic circulatory arrest + Cirp-/- group (Cirp-/- group). Murine microglial BV2 cells were administered by adeno-associated viral vectors containing cold-inducible RNA-binding protein small interference RNA or negative control small interference RNA at 2 days before 4-hour oxygen-glucose deprivation at 18°C. Microglial activation, cell death, neuroinflammation, and related protein expression were assessed in tissue samples and cell cultures.

Cold-inducible RNA-binding protein was elevated along with evident neuroinflammation and neuronal damage in rats exposed to deep hypothermic circulatory arrest. In Cirp-/- rats, histologic injury (3.00 [interquartile range, 2.00-3.00] vs 1.00 [interquartile range, 1.00-1.50] neuropathological score, P < .001) and microglial activation (40 ± 4 vs 13 ± 7 CA1 area, P < .001) were alleviated after deep hypothermic circulatory arrest. With RNA-sequencing analysis, this associated with reduction of key proinflammatory cytokines induced by inhibiting Brd2-NF-κB signals. In BV2 cells treated with small interference RNA-cold-inducible RNA-binding protein, similar protective effects were observed, including decreased proinflammatory cytokines and cytotoxicity. Brd2-NF-κB signals were confirmed by the addition of Brd2 inhibitor JQ1. Notably, the conditioned medium from BV2 cells transfected with small interference RNA cold-inducible RNA-binding protein significantly reduced apoptosis in neural SH-SY5Y cells after oxygen-glucose deprivation, which was similar to that after JQ1 administration. Conclusions: Enhanced cold-inducible RNA-binding protein in microglia aggravates neuronal injury by promoting the release of proinflammatory cytokines, which might be mediated through Brd2-NF-κB signals during deep hypothermic circulatory arrest.