STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.

Autor:	Woo MS; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Mayer C; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Binkle-Ladisch L; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Sonner JK; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Rosenkranz SC; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Shaposhnykov A; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Rothammer N; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Tsvilovskyy V; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Lorenz SM; Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany., Raich L; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Bal LC; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Vieira V; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Wagner I; Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University and University Hospital of Geneva, Geneva, Switzerland., Bauer S; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Glatzel M; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Conrad M; Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany., Merkler D; Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University and University Hospital of Geneva, Geneva, Switzerland., Freichel M; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany., Friese MA; Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: manuel.friese@zmnh.uni-hamburg.de.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Jul 25; Vol. 187 (15), pp. 4043-4060.e30. Date of Electronic Publication: 2024 Jun 14.
DOI:	10.1016/j.cell.2024.05.031
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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