Microglia derived cold-inducible RNA-binding protein play a critical role in neuroinflammation and neuronal damage after cardiac arrest and resuscitation in rats.

Cardiac arrest (CA) is a global health problem that accounts for more deaths than many other diseases. Global cerebral ischemia-reperfusion injury resulting from CA and resuscitation remains a critical issue that urgently requires further investigation. Neuroinflammation-related cytokines play a central role in exacerbating neuronal injury in conditions involving global cerebral ischemia-reperfusion. As a newly discovered damage-associated molecular pattern (DAMP), cold-inducible RNA-binding protein (CIRP) contributes significantly to various inflammatory diseases. However, the mechanism of CIRP in cardiac arrest and resuscitation associated neuroinflammation remains unclear. This study aims to investigate the role of microglia derived CIRP in neuroinflammation and neuron damage. We established a rat model of CA and hippocampal neuron/BV2 microglia cells oxygen-glucose deprivation/reoxygenation (OGDR) model. In animal experiments, we observed an increase in CIRP expression of hippocampus after CA and resuscitation. Moreover, elevated CIRP level can activate microglia to release more inflammatory factors, thereby damaging neurons. RNA sequencing analysis indicated that the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway may serve as a downstream pro-inflammatory signaling pathway of CIRP. In cell experiments, microglial cells subjected to OGDR secreted numerous exosomes containing CIRP. These exosomes acted on the cells' own inflammatory pathways in an autocrine manner, intensifying the inflammatory response. Moreover, they directly damaged neighboring neurons through paracrine action. Inhibiting the synthesis or secretion of CIRP alleviated neuroinflammation. This study enhances to understand the role of CIRP in the neuroinflammation induced by global cerebral ischemia reperfusion and has identifies potential targets for brain resuscitation therapy following CA.