Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein

• Published in: Cell reports (Cambridge) Vol. 38; no. 7; p. 110358
• Main Authors: Sterling, Jacob K., Kam, Tae-In, Guttha, Samyuktha, Park, Hyejin, Baumann, Bailey, Mehrabani-Tabari, Amir A., Schultz, Hannah, Anderson, Brandon, Alnemri, Ahab, Chou, Shih-Ching, Troncoso, Juan C., Dawson, Valina L., Dawson, Ted M., Dunaief, Joshua L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-02-2022
• Subjects: alpha-Synuclein - toxicity; Animals; Behavior, Animal - drug effects; cellular iron sequestration response; Disease Models, Animal; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Female; interleukin 6; Interleukin-6 - metabolism; iron; Iron - metabolism; Iron Chelating Agents - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; microglia; Nerve Degeneration - pathology; neurodegeneration; neuroinflammation; Neurons - metabolism; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson's disease; Signal Transduction - drug effects; Substantia Nigra - drug effects; Substantia Nigra - pathology; α-synuclein; interleukin 6; cellular iron sequestration response; Parkinson's disease; neuroinflammation; neurodegeneration; iron; microglia; α-synuclein
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110358

α-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson's disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.
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•Pathological α-synuclein triggers production of IL-6•IL-6 drives the toxic neuronal iron sequestration response in vitro and in vivo•Blockade of the CISR pathway is partially protective in models of synucleinopathy•Hallmarks of CISR are seen in Parkinson's disease
Inflammation contributes to neurodegeneration in Parkinson's disease. Sterling et al. describe the activation of nutritional immunity by pathological α-synuclein. Through this pathway, termed the cellular iron sequestration response (CISR), pro-inflammatory microglia drive neuronal iron accumulation and cell death.