〔Abstract〕 Objective To investigate whether GIV, a coiled helix structural domain protein containing 88A, has an effect on the neuroinflammatory response in a model of cerebral ischemia-reperfusion injury. Methods A middle cerebral artery embolization-reperfusion model(MACO/R) and an oxygen glucose deprivation/reoxygenation model(OGD 6 h+R 24 h) of BV2 microglia were constructed in C57BL/6 mice, and the area of cerebral infarction was detected by TTC staining; the Longa neurobiological score was used to evaluate the degree of neurological deficit in mice; ELISA was used to detect the release of IL-6 and TNF-α in the supernatant of peripheral blood and cell cultures, and Western blot was used to detect the protein expression of GIV, TREM2 and TLR4 in the cortical area around the infarct foci in mice; different concentrations of lipopolysaccharide(LPS, 1, 5, 10 μg/ml) were used to stimulate BV2 cells for 24 h to establish a neuroinflammation model, qRT-PCR was performed to detect the mRNA levels of IL-6, TNF-α and IL-1β, and Western blot was used to detect the expression of GIV; OGD/R culture treatment was performed after knocking down the expression of GIV gene using siRNA interference technique; ELISA was performed to detect the release concentration of IL-6 and TNF-α in cell culture medium supernatant; protein immunoblotting was performed to detect the knockdown efficiency of GIV. Results Both the successfully constructed MCAO/R and OGD/R models activated the neuroinflammatory response and induced a decrease in protein expression of GIV; MCAO/R induced increased concentrations of IL-6 and TNF-α release in peripheral blood of mice and promoted the protein expression of TREM2 and TLR4; LPS activated IL-6, IL-1β and TNF-α expression in BV2 cells, but did not affect GIV expression; siRNA interference with GIV gene expression further increased the expression of inflammatory factors IL-6 and TNF-α.Conclusion The GIV gene may be characteristically involved in regulating the neuroinflammatory response induced by cerebral ischemia-reperfusion injury, and it may be a potential therapeutic target for cerebral ischemia-reperfusion injury.