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Woo, M.S.* ; Mayer, C.* ; Binkle-Ladisch, L.* ; Sonner, J.K.* ; Rosenkranz, S.C.* ; Shaposhnykov, A.* ; Rothammer, N.* ; Tsvilovskyy, V.* ; Lorenz, S. ; Raich, L.* ; Bal, L.C.* ; Vieira, V.* ; Wagner, I.* ; Bauer, S.* ; Glatzel, M.* ; Conrad, M. ; Merkler, D.* ; Freichel, M.* ; Friese, M.A.*

STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.

Cell 187, 4043-4060.e30 (2024)
Publ. Version/Full Text DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Sting ; Calcium Signaling ; Cell Death ; Excitotoxicity ; Ferroptosis ; Multiple Sclerosis ; Neurodegeneration ; Neuroinflammation; Cyclic Gmp-amp; T-cells; Dna; Activation; Degeneration; Ferroptosis; Synthase; Release; Sensor; Stim1
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 187, Issue: 15, Pages: 4043-4060.e30 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
Grants Hertie-Stiftung
Memorial Stipend
DOI 10.1016/j.cell.2024.05.031
WOS ID 001282248700001
Scopus ID 85197041595
PubMed ID 38878778
Erfassungsdatum 2024-06-18
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