Abstract Body: Background: Neuroinflammation-induced injury is closely related to poor prognosis in patients with brain injury after cardiopulmonary resuscitation.The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) axis is a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as a crucial mediator of neuroinflammation in ischemic stroke. However, the role of the cGAS-STING pathway in regulating inflammation in post-cardiopulmonary resuscitation brain injury and the underlying mechanisms involved remain unclear.
Methods: The cardiac arrest(CA) model of C57BL/6J male mice was induced by transesophageal electric shock. To evaluate the role of the cGAS-STING pathway in brain injury after cardiac arrest in Sting-deficiency (Sting^-/-) mice. In addition, intraperitoneally administered STING inhibitor H151 evaluated the role of the cGAS-STING pathway in brain injury after cardiac arrest in mice.
Results: In the mice CA model, we observed significant activation of the cGAS-STING pathway, mainly in mouse brain neurons and microglia. Brain injury after cardiac arrest triggers the release of dsDNA into the cytoplasm and triggers an inflammatory response by activating the cGAS-STING axis. Knockout of STING can reduce the activation of cGAS-STING pathway and the level of downstream inflammatory cytokines in brain injury after cardiopulmonary resuscitation, while maintaining the expression of blood-brain barrier related proteins (occludin, cluadin-5, ZO-1). In addition, H151 can reduce the activation of cGAS-STING pathway and the level of downstream inflammatory cytokines in brain injury after cardiopulmonary resuscitation in mice, and restore the expression of blood-brain barrier related proteins (occludin, cluadin-5, ZO-1).
Conclusions: Our data suggest that inhibiting the cGAS-STING pathway reduces the neuroinflammatory burden of brain injury after cardiopulmonary resuscitation, and inhibiting or missing STING preserves blood-brain barrier integrity after cardiac arrest and cardiopulmonary resuscitation, and highlight this approach as a potential treatment strategy for brain injury-mediated pathology after cardiopulmonary resuscitation.
Keywords: Neuroinflammation; STING; cGAS, Blood-brain barrier, Neurons