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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). Howe...

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Main Authors: Woo, Marcel Seungsu (Author) , Mayer, Christina (Author) , Binkle-Ladisch, Lars (Author) , Sonner, Jana K. (Author) , Rosenkranz, Sina C. (Author) , Shaposhnykov, Artem (Author) , Rothammer, Nicola (Author) , Tsvilovskyy, Volodymyr (Author) , Lorenz, Svenja M. (Author) , Raich, Lukas (Author) , Bal, Lukas C. (Author) , Vieira, Vanessa (Author) , Wagner, Ingrid (Author) , Bauer, Simone (Author) , Glatzel, Markus (Author) , Conrad, Marcus (Author) , Merkler, Doron (Author) , Freichel, Marc (Author) , Friese, Manuel A. (Author)
Format: Article (Journal)
Language:English
Published: 25 July 2024
In: Cell
Year: 2024, Volume: 187, Issue: 15, Pages: 4043-4060.e30
ISSN:1097-4172
DOI:10.1016/j.cell.2024.05.031
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.cell.2024.05.031
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S0092867424005762
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Author Notes:Marcel S. Woo, Christina Mayer, Lars Binkle-Ladisch, Jana K. Sonner, Sina C. Rosenkranz, Artem Shaposhnykov, Nicola Rothammer, Volodymyr Tsvilovskyy, Svenja M. Lorenz, Lukas Raich, Lukas C. Bal, Vanessa Vieira, Ingrid Wagner, Simone Bauer, Markus Glatzel, Marcus Conrad, Doron Merkler, Marc Freichel, Manuel A. Friese
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Summary: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.
Item Description:Online verfügbar: 14. Juni 2024, Artikelversion: 25. Juli 2024
Gesehen am 03.03.2025
Physical Description:Online Resource
ISSN:1097-4172
DOI:10.1016/j.cell.2024.05.031

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