High-salt diet does not boost neuroinflammation and neurodegeneration in a model of α-synucleinopathy

Heras‐Garvin, Antonio; Refolo, Violetta; Reindl, Markus; Wenning, Gregor K.; Stefanova, Nadia

doi:10.1186/s12974-020-1714-y

Cited by 13 publications

(8 citation statements)

References 92 publications

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“…While we cannot exclude the possibility that our experimental strategies were insufficient to characterize the complete responses of microglia to HSD, no study has yet reported that either sterile inflammatory ligands or diet‐induced systemic inflammation induces immunological memory in tissue‐resident macrophages (Dominguez‐Andres et al , 2022). Given that the effects of HSD on microglia and macrophage polarization remain debatable (Amara et al , 2016; Heras‐Garvin et al , 2020; Zhang et al , 2020), future work evaluating microglial responses through high‐throughput sequencing could be informative. Investigation of whether innate immune memory can be triggered in different tissue‐resident macrophage populations after HSD and the contribution of these populations to disease progression represents a fascinating area of research.…”

Section: Discussionmentioning

confidence: 99%

Trained immunity induced by high‐salt diet impedes stroke recovery

Lin,

Jiang,

Chen

et al. 2023

EMBO Reports

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A high‐salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long‐term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte‐derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD‐fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD‐induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD‐induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Trained immunity induced by high‐salt diet impedes stroke recovery

Lin,

Jiang,

Chen

et al. 2023

EMBO Reports

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“…Bilateral hippocampal CA3 and DG fields of three 15 μm-thick consecutive coronal sections corresponding to bregma 1.82 mm to bregma 2.46 mm were captured at 20× magnification and digitized. The percentage of positively stained areas of Iba1, IL-1β, IL-6 or caspase 8 was quantified using ImageJ [ 19 ]. Three independent experiments were performed, and data was averaged per slide before statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

miR-203, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling

et al. 2022

J Neuroinflammation

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Background miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA. Methods Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3ʹUTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test. Results Akirin2, an activator of NF‐κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF‐κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF‐κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF‐κB, IL-1β and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus. Conclusion A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF‐κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling.

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“…The deviation was found to be accompanied by an increase of CD3 + , CD4 + and CD8 + in the same regions. Interestingly, an increased salt diet activated inflammation in various diseases, but does not induce neuroinflammation and neurodegeneration in α-synucleinopathies [ 231 ]. It is also stressed that the elevated iNOS expression in MSA is correlated with neuroinflammation and neuronal loss [ 232 ].…”

Section: Various Neurodegenerative Factorsmentioning

confidence: 99%

Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences

Koziorowski

Figura

Milanowski

et al. 2021

Cells

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Parkinson's disease (PD), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) belong to a group of neurodegenerative diseases called parkinsonian syndromes. They share several clinical, neuropathological and genetic features. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra- and intracellular accumulation of misfolded proteins. The parkinsonian diseases affect distinct areas of the brain. PD and MSA belong to a group of synucleinopathies that are characterized by the presence of fibrillary aggregates of α-synuclein protein in the cytoplasm of selected populations of neurons and glial cells. PSP is a tauopathy associated with the pathological aggregation of the microtubule associated tau protein. Although PD is common in the world's aging population and has been extensively studied, the exact mechanisms of the neurodegeneration are still not fully understood. Growing evidence indicates that parkinsonian disorders to some extent share a genetic background, with two key components identified so far: the microtubule associated tau protein gene (MAPT) and the α-synuclein gene (SNCA). The main pathways of parkinsonian neurodegeneration described in the literature are the protein and mitochondrial pathways. The factors that lead to neurodegeneration are primarily environmental toxins, inflammatory factors, oxidative stress and traumatic brain injury.

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High-salt diet does not boost neuroinflammation and neurodegeneration in a model of α-synucleinopathy

Cited by 13 publications

References 92 publications

Trained immunity induced by high‐salt diet impedes stroke recovery

Trained immunity induced by high‐salt diet impedes stroke recovery

miR-203, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling

Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences

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