STING orchestrates the neuronal inflammatory stress response in multiple sclerosis

Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that…

• JH
  Joachim Herz Stiftung

  Award: 850035
• DF
  Deutsche Forschungsgemeinschaft

  Awards: FOR 2289 (FR1720/9-1, FR1638/3-1, CO291/10-1, CO291/9-1, FR1638/3-2, FR1720/9-1, SPP 2306, FOR2289, FR1720/9-2
• EK
  Else Kröner-Fresenius-Stiftung

  Award: 2023_EKMS.03
• GH
  Gemeinnützige Hertie-Stiftung

  Award: P1180046
• DM
  Deutschen Multiple Sklerose Gesellschaft

  Award: V 6.2
• ER
  European Research Council

  Award: GA 884754