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

Area of Science:

• Neuroscience
• Immunology
• Cellular Biology

Background:

• Ischemic stroke triggers excessive immune responses linked to poor outcomes.
• Regulatory T cells (Tregs) are key immunomodulators, but their role in stroke recovery is not fully understood.

Purpose of the Study:

• To elucidate the mechanisms by which Tregs promote neurological recovery post-stroke.
• To investigate the role of the astrocyte-neuron lactate shuttle (ANLS) and the STING pathway in Treg-mediated neuroprotection.

Main Methods:

• Behavioral tests, histological staining (HE, Nissl, LFB) assessed neurological recovery and neuronal remodeling.
• Immunofluorescence, Western blot, lactate, ATP assays, and cell viability assays evaluated the astrocyte-neuron lactate shuttle (ANLS) and monocarboxylate transporter (MCT) function.
• Western blot analyzed stimulator of interferon gene (STING) pathway activation.

Main Results:

• Tregs reduced neuronal injury, enhanced synaptic plasticity, promoted myelin repair, and improved cognitive and motor functions.
• Tregs boosted MCT-mediated lactate transfer to neurons, supplying energy for remodeling, an effect reversed by the MCT inhibitor 4-CIN.
• Tregs suppressed STING pathway activation, while STING activation by DMXAA blocked Treg-induced ANLS potentiation.

Conclusions:

• Tregs promote long-term neurological recovery after stroke by enhancing the astrocyte-neuron lactate shuttle (ANLS) for neuronal remodeling.
• This neuroprotection is mediated by the inhibition of the STING pathway, representing a novel therapeutic mechanism.