In multiple sclerosis (MS), persistent inflammation results in neurodegeneration that is driven by immune cells, microglia and astrocytes, with active neuronal inflammation also suggested to have a crucial involvement. In Cell, Woo et al. report that stimulator of interferon genes (STING) controls the neuronal inflammatory stress response in MS, and that targeting STING in neurons could protect from inflammation-induced neurodegeneration. Mice with neuronal-specific deletion of the ER transmembrane calcium-sensor protein STIM1 developed more severe experimental autoimmune encephalomyelitis (EAE). In vitro, Stim1-deficient neurons were more susceptible to cell death but only if neurons were exposed to IFNγ. After IFNγ exposure and during EAE, neurons were found to express STING, and STING colocalized with STIM1 at the ER and detached during glutamate excitotoxicity. Neurons expressing STING were more vulnerable to glutamate excitotoxicity. There was increased autophagy in neurons expressing STING or after exposure to IFNγ, and increased STING-dependent autophagy in Stim1-deficient neurons. Ferroptosis is induced in cancer cells by autophagic degradation of GPX4. After exposure to glutamate, GPX4 levels in neurons diminished rapidly and this reduction was higher in neurons expressing STING. The authors also found increased levels of STING in neurons of individuals with MS. Neuron-specific deletion of Sting1 or treatment with STING inhibitors in EAE mice ameliorated the disease course and protected them from neuronal loss. Together, the authors suggest that STING regulates the neuronal inflammatory stress response during MS.
Original reference: Cell https://doi.org/10.1016/j.cell.2024.05.031 (2024)
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