Tregs Promote Astrocyte-Neuron Lactate Shuttle via Inhibiting STING Pathway to Improve Neurological Recovery After Ischemic Stroke

Background: Excessive immune response following ischemic stroke is closely associated with poor clinical prognosis. Although regulatory T cell (Treg) is recognized as pivotal immunomodulator, its potential mechanisms in post-stroke neurological recovery and immunotherapy remain unclear.

Methods: Neurological recovery and neuronal remodeling were investigated by behavior tests, HE staining, Nissl staining, and LFB staining. Monocarboxylate Transporter (MCT) was detected to evaluate the role of astrocyte-neuron lactate shuttle (ANLS) in Tregs-mediated neuroprotection by immunofluorescence and western blot, lactate assay, ATP assay, and cell viability assay experiments. The expression of stimulator of interferon gene (STING) and phosphorylation of downstream factors were examined by western blot.

Results: Tregs significantly attenuated neuronal injury, upregulated the expression of synaptic plasticity-related proteins, promoted myelin reconstruction, and improved spatial cognition, memory function, and motor coordination. Mechanistically, Tregs enhanced MCT-mediated lactate transfer to neurons, providing energy supply for neuronal remodeling, whereas the MCT inhibitor 4-CIN reversed Tregs-mediated neuroprotection. In addition, Tregs suppressed the activation of the STING pathway, and activation of STING by DMXAA abolished the Tregs-induced potentiation of ANLS.

Conclusions: This study clarifies a novel mechanism by which Tregs promote ANLS and provide energy supply for neuronal remodeling by inhibiting the STING pathway, thereby improving the long-term neurological recovery after stroke.

STING; Tregs; astrocyte‐neuron lactate shuttle; ischemic stroke; neurological recovery.