cGAS/STING and innate brain inflammation following acute high-fat feeding

Elzinga, Sarah; Henn, Rosemary E.; Murdock, Benjamin J.; Kim, Bhumsoo; Hayes, John M.; Mendelson, Faye E.; Webber-Davis, Ian; Teener, Sam; Pacut, Crystal; Lentz, Stephen I.; Feldman, Eva L.

doi:10.3389/fimmu.2022.1012594

Cited by 17 publications

(27 citation statements)

References 87 publications

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“…In addition, a positive correlation was observed between the body weight and microglial numbers, indicating that increased obesity is associated with a greater number of hippocampal microglia. These findings align with our recent report where we show changes in hippocampal microglial activation as measured by microglial morphology after only 4 days using this model of HFD induced obesity and prediabetes [ 58 ]. Other have similarly shown that HFD causes robust changes in microglial activation as measured by changes in morphology [ 12 , 22 , 55 , 59 , 60 ], phagocytosis or phagocytic markers [ 12 , 22 , 60 ], and microglial numbers or density [ 12 , 60 , 61 ].…”

Section: Discussionsupporting

confidence: 93%

“…ELISA was performed by the University of Michigan Immune Monitoring Core of the Rogel Cancer Center. Terminal IHC for analysis of hippocampal microglial infiltration was performed on cohort 3 hemi brains similar to previous [ 58 ]. In brief, following sacrifice, hemi-brains were dissected and fixed in 4% paraformaldehyde for a minimum of 48 h, then passed through a sucrose gradient.…”

Section: Cognitive Phenotypingmentioning

confidence: 99%

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Obesity-induced neuroinflammation and cognitive impairment in young adult versus middle-aged mice

et al. 2022

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Background Obesity rates are increasing worldwide. Obesity leads to many complications, including predisposing individuals to the development of cognitive impairment as they age. Immune dysregulation, including inflammaging (e.g., increased circulating cytokines) and immunosenescence (declining immune system function), commonly occur in obesity and aging and may impact cognitive impairment. As such, immune system changes across the lifespan may impact the effects of obesity on neuroinflammation and associated cognitive impairment. However, the role of age in obesity-induced neuroinflammation and cognitive impairment is unclear. To further define this putative relationship, the current study examined metabolic and inflammatory profiles, along with cognitive changes using a high-fat diet (HFD) mouse model of obesity. Results First, HFD promoted age-related changes in hippocampal gene expression. Given this early HFD-induced aging phenotype, we fed HFD to young adult and middle-aged mice to determine the effect of age on inflammatory responses, metabolic profile, and cognitive function. As anticipated, HFD caused a dysmetabolic phenotype in both age groups. However, older age exacerbated HFD cognitive and neuroinflammatory changes, with a bi-directional regulation of hippocampal inflammatory gene expression. Conclusions Collectively, these data indicate that HFD promotes an early aging phenotype in the brain, which is suggestive of inflammaging and immunosenescence. Furthermore, age significantly compounded the impact of HFD on cognitive outcomes and on the regulation of neuroinflammatory programs in the brain.

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Section: Discussionsupporting

confidence: 93%

Section: Cognitive Phenotypingmentioning

confidence: 99%

Obesity-induced neuroinflammation and cognitive impairment in young adult versus middle-aged mice

et al. 2022

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“…[15][16][17] The cGAS/STING system is one such innate inflammatory route connected to the cellular response to metabolic dysfunction. [18][19][20] In a mouse model of Parkinson's disease (PD) as well in the Substantia Nigra of human patients with PD, the activation of STING leads accumulation of α-synuclein and subsequent neurodegeneration and neuroinflammation. Mice deficient in STING were protected from loss of dopaminergic neurons while α-synuclein aggregates increase STING expression.…”

Section: S Ting In the Cn S And Neuro Inf L A M M At I O Nmentioning

confidence: 99%

“…23 These studies demonstrate a role for innate immune systems and the cGAS/STING pathway in mediating metabolic disequilibriuminduced CNS dysfunction. 18 In CNS injury, STING signaling is elevated and is involved in uncontrolled inflammatory processes such as that seen in traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the STING-regulated signaling activity that affects CNS damage remains unclear; together with cytokine production, STING signaling is implicated in cell death pathways such as autophagy, necroptosis, ferroptosis, and pyroptosis.…”

Section: S Ting In the Cn S And Neuro Inf L A M M At I O Nmentioning

confidence: 99%

“…Metabolic dysfunction induces dysregulation of CNS immunological and inflammatory systems and is associated with enhanced glial activation and heightened production of CNS pro‐inflammatory proteins and mediators 15–17 . The cGAS/STING system is one such innate inflammatory route connected to the cellular response to metabolic dysfunction 18–20 . In a mouse model of Parkinson's disease (PD) as well in the Substantia Nigra of human patients with PD, the activation of STING leads accumulation of α‐synuclein and subsequent neurodegeneration and neuroinflammation.…”

Section: Sting In the Cns And Neuroinflammationmentioning

confidence: 99%

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Role of stimulator of interferon genes (STING) in the enteric nervous system in health and disease

Balasubramaniam

Srinivasan

2023

Neurogastroenterology Motil

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Stimulator of Interferon Genes (STING) is a crucial protein that controls the immune system's reaction to bacterial and viral infections. As a pattern‐recognition receptor, STING is found in immune cells as well as in neurons and glia in the enteric nervous system (ENS). Recent studies have linked STING to the pathogenesis of several neurological disorders like multiple sclerosis (MS), Alzheimer's disease (AD), and gastrointestinal disorders, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), which are characterized by chronic inflammation and dysregulation of the enteric nervous system (ENS) in the digestive tract. STING plays a crucial role in the pathway that induces the production of interferon in response to viral infection in the central nervous system (CNS). A new study by Dharshika et al. in the current issue of Neurogastroenterology and Motility has demonstrated distinct roles for STING in enteric neurons and glia, namely activation of STING leads to IFN‐β production in enteric neurons but not in glia and reducing STING activation in enteric glia does not modulate the severity of Dextran sulfate sodium (DSS) colitis or subsequent loss of enteric neurons. Rather, the role of STING in enteric glia is related to enhancing autophagy. STING can influence gastrointestinal motility and barrier function and therefore be involved in the pathophysiology of IBS and IBD. This mini review highlights the current knowledge of STING in the pathophysiology of CNS and gastrointestinal diseases as well as these newly uncovered roles STING in enteric neurons and glia.

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Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease

Kim,

Kang,

Mendelson

et al. 2023

J of Extracellular Vesicle

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The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops from a diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate‐ and glucose‐induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitate‐treated oligodendrocytes enhance insulin resistance in recipient neurons. Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease in MetS mediated by EVs, which spread Alzheimer's pathology and insulin resistance.

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cGAS/STING and innate brain inflammation following acute high-fat feeding

Cited by 17 publications

References 87 publications

Obesity-induced neuroinflammation and cognitive impairment in young adult versus middle-aged mice

Obesity-induced neuroinflammation and cognitive impairment in young adult versus middle-aged mice

Role of stimulator of interferon genes (STING) in the enteric nervous system in health and disease

Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease

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