STING orchestrates the neuronal inflammatory stress response in multiple sclerosis

• Published in: Cell Vol. 187; no. 15; pp. 4043 - 4060.e30
• Main Authors: Woo, Marcel S., Mayer, Christina, Binkle-Ladisch, Lars, Sonner, Jana K., Rosenkranz, Sina C., Shaposhnykov, Artem, Rothammer, Nicola, Tsvilovskyy, Volodymyr, Lorenz, Svenja M., Raich, Lukas, Bal, Lukas C., Vieira, Vanessa, Wagner, Ingrid, Bauer, Simone, Glatzel, Markus, Conrad, Marcus, Merkler, Doron, Freichel, Marc, Friese, Manuel A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2024
• Subjects: Animals; Autophagy; calcium signaling; cell death; Disease Models, Animal; excitotoxicity; Female; Ferroptosis; Glutamic Acid - metabolism; Humans; Inflammation - metabolism; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; multiple sclerosis; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; neurodegeneration; neuroinflammation; Neurons - metabolism; Neurons - pathology; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Signal Transduction; STING; ferroptosis; cell death; neuroinflammation; multiple sclerosis; calcium signaling; neurodegeneration; STING; excitotoxicity
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2024.05.031

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 target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS. [Display omitted] •STING is expressed in human and mouse neurons solely under inflammatory conditions•Excitotoxicity activates a non-canonical STIM1-STING signaling pathway in neurons•Neuronal STING activation leads to autophagic GPX4 degradation and ferroptosis•Targeting neuronal STING protects from inflammation-induced neurodegeneration Inflammation and glutamate excitotoxicity are the major drivers of neuronal cell death in multiple sclerosis (MS). This study identifies neuronal STING as a central regulator of inflammation-induced neurodegeneration by integrating (1) interferon and (2) glutamate-evoked intracellular calcium signaling to induce ferroptotic cell death, offering a target for treating MS-related neurodegeneration.