Skip to main content
Publications of the Week

Suppressing Interferon Gamma Stimulates Microglial Responses and Repair of Microbleeds in the Diabetic Brain

By September 26, 2018No Comments

Microcirculatory damage is a common complication for those with vascular risk factors such as diabetes. In order to resolve vascular insults, the brain’s immune cells (microglia) must rapidly envelop the site of injury. Currently it is unknown whether type 1 diabetes, a condition associated with chronic immune system dysfunction, alters microglial responses to damage and what mechanisms are responsible. Using in vivo two-photon microscopy in adult male mice, we show that microglial envelopment of laser induced cerebral microbleeds is diminished in a hyperglycemic mouse model of type 1 diabetes, which could not be fully rescued with chronic insulin treatment. Microglia were important for vessel repair since reduced microglial accumulation in diabetic mice or near complete depletion in healthy controls was associated with greater secondary leakage of the damaged vessel. Broadly suppressing inflammation with dexamethasone (DEX) in diabetic mice but not healthy controls, significantly enhanced microglial responses to microbleeds and attenuated secondary vessel leakage. These enhancements were associated with changes in interferon gamma (IFNγ) signalling since DEX suppressed abnormally high levels of IFNγ protein levels in brain and blood serum of diabetic mice. Further, blocking IFNγ in diabetic mice with neutralizing antibodies restored normal microglial chemotaxic responses and purinoceptor P2YR12 gene expression, as well as mitigated secondary leakage. These results suggest that abnormal IFNγ signalling disrupts microglial function in the diabetic brain, and that immunotherapies targeting IFNγ can stimulate microglial repair of damaged vessels.Significance statement: Although type 1 diabetes is an established risk factor for vascular complications such as microbleeds and is known to hinder wound healing in the body, no study has examined how diabetes impacts the brain’s innate immune reparative response (involving cells called microglia) to vascular injury. Here we show that microglial responses to brain microbleeds were diminished in diabetic animals, which also exacerbated secondary leakage from damaged vessels. These impairments were related to abnormally high levels of the pro-inflammatory cytokine interferon gamma (IFNγ), since reducing IFNγ with immunosuppressant drugs or blocking antibodies helped restore normal microglial responses and repair of damaged vessels. These data highlight the use of IFN modulating therapeutics to enhance vascular repair in at-risk populations.