GPR84 exacerbates blood-brain barrier disruption after ischemic stroke via cAMP/CREB-dependent tight junction suppression

Compromise of the blood-brain barrier represents a pivotal event in ischemic stroke pathology, though the specific inflammatory mediators involved remain incompletely characterized. We postulated a role for the inflammatory G protein-coupled receptor GPR84 in driving this process. Experimental cerebral ischemia in mice provoked a marked increase in cortical GPR84 expression. A corresponding upregulation was observed in human cerebral microvascular endothelial cells subjected to oxygen-glucose deprivation and recovery. Mice lacking the Gpr84 gene demonstrated a pronounced protective phenotype following ischemic insult, featuring limited tissue infarction, diminished brain swelling, superior performance on neurological assessments, and significantly reduced vascular leakage. Preservation of the structural proteins Claudin-5 and ZO-1 at the neurovascular unit was evident. Application of selective GPR84 agonists to endothelial monolayers recapitulated barrier failure, an effect abrogated by co-administration of a cell-permeable cAMP analogue. Silencing of GPR84 expression conferred resistance to barrier dysfunction and was linked to maintained phosphorylation of the transcription factor CREB. This work delineates a cell‑autonomous GPR84‑cAMP‑CREB signaling cascade that directly impairs brain endothelial barrier function. The integrated contributions of GPR84 expressed on immune cells within the neurovascular unit in vivo remain to be defined. These results suggest GPR84 as a candidate mechanistic target for barrier preservation strategies.