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

TL;DR

Regulatory T cells (Tregs) help improve recovery after stroke by boosting energy transfer to brain cells through a process called ANLS, which is achieved by inhibiting the STING pathway.

Contribution

This study reveals a new mechanism where Tregs enhance neurological recovery after stroke by promoting the astrocyte-neuron lactate shuttle via STING pathway inhibition.

Findings

Tregs reduce neuronal injury and improve cognitive and motor functions after stroke.

Tregs enhance lactate transfer to neurons via MCTs, supporting neuronal remodeling.

Tregs suppress the STING pathway, and STING activation counteracts their beneficial effects.

Abstract

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.

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.

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.

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.

Tregs improve long‐term neurological recovery after ischemic stroke. Tregs promote ANLS and provide energy supply for neuronal remodeling after stroke. The mechanism underlying Tregs‐mediated ANLS enhancement involves suppression of the STING pathway.

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