STING-GDF15-STAT3 signaling contributes to neuroinflammation after intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a devastating subtype of stroke associated with high mortality and long-term disability, for which effective treatments remain limited. Activation of the stimulator of interferon genes (STING) pathway has been implicated in neuroinflammation after ICH; however, the downstream molecular mechanisms remain poorly defined. This study investigated the role of STING signaling in ICH pathogenesis, with a particular focus on microglia-associated inflammatory responses. METHODS: Transcriptomic profiling of human and murine ICH samples was conducted to identify downstream effectors of STING signaling. Plasma STING levels were measured in patients with ICH and analyzed for correlations with clinical severity. A collagenase IV-induced ICH mouse model was employed to investigate the functional role of STING through genetic ablation and pharmacological modulation using the STING inhibitor H151 or the agonist DMXAA. Mechanistic studies were further conducted in hemin-stimulated microglial cells, and the therapeutic effect of GDF15 neutralization was evaluated using intracerebroventricular administration of ponsegromab (Pon). RESULTS: STING expression was significantly increased in human and murine ICH tissues and was mainly localized to microglia. Plasma STING levels were positively associated with disease severity in patients with ICH. Inhibition or deletion of STING reduced GDF15 expression, attenuated neuroinflammation, and alleviated brain injury, whereas STING activation worsened neuronal damage and neurological deficits. In vitro, STING activation in hemin-treated microglia enhanced GDF15 expression, STAT3 phosphorylation, oxidative stress, and inflammatory cytokine production. Notably, neutralization of GDF15 significantly ameliotated neuroinflammation, reduced brain edema, and improved behavioral impairments after ICH. Furthermore, intracerebroventricular administration of the anti-GDF15 monoclonal antibody Pon markedly improved behavioral performance and attenuated secondary brain injury after ICH. CONCLUSION: These findings suggest that the STING-GDF15-STAT3 signaling axis contributes to neuroinflammatory responses and secondary brain injury after ICH, and may represent a potential therapeutic target for haemorrhagic stroke.