Microglial NLRP3 Inflammasome Induces Excitatory Synaptic Loss Through IL-1β-Enriched Microvesicle Release: Implications for Sepsis-Associated Encephalopathy

Moraes, Carolina A.; Hottz, Eugênio D.; Ornellas, Débora dos Santos; Adesse, Daniel; Azevedo, Carolina Trindade de; d'Avila, Joana C; Zaverucha-do-Valle, Camila; Maron‐Gutierrez, Tatiana; Barbosa, Helene Santos; Bozza, Patrı́cia T.; Bozza, Fernando A.

doi:10.1007/s12035-022-03067-z

Cited by 16 publications

(9 citation statements)

References 41 publications

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“…Lymphotoxin-α (LT-α), the non-canonical ligand of TNFR1, whose canonical ligand is TNF, was increased only in male retinas 6h after LPS administration. IL1-β, secreted by macrophages through inflammasome activation after LPS challenge ( 54 ), was significantly upregulated in the plasma of females and males at 24h, while this increase was observed in the retina at 24h in females and 72h in males.…”

Section: Resultsmentioning

confidence: 99%

Retinal response to systemic inflammation differs between sexes and neurons

Rodríguez-Ramírez,

Norte-Muñoz,

Lucas-Ruiz

et al. 2024

Front. Immunol.

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BackgroundNeurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) on the retina of male and female mice and determine whether antagonism of the NLRP3 inflammasome and the extrinsic pathway of apoptosis have protective effects on the retina.MethodsA single intraperitoneal injection of LPS (5 mg/kg) was administered to two months old C57BL/6J male and female mice. Retinas were examined longitudinally in vivo using electroretinography and spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival and microglial activation were analysed in flat-mounts. Retinal extracts were used for flow cytometric analysis of CD45 and CD11b positive cells. Matched plasma and retinal levels of proinflammatory cytokines were measured by ELISA. Retinal function and RGC survival were assessed in animals treated with P2X7R and TNFR1 antagonists alone or in combination.ResultsIn LPS-treated animals of both sexes, there was transient retinal dysfunction, loss of vision-forming but not non-vision forming RGCs, retinal swelling, microglial activation, cell infiltration, and increases in TNF and IL-1β. Compared to females, males showed higher vision-forming RGC death, slower functional recovery, and overexpression of lymphotoxin alpha in their retinas. P2X7R and TNFR1 antagonism, alone or in combination, rescued vision-forming RGCs. P2X7R antagonism also rescued retinal function. Response to treatment was better in females than in males.ConclusionsSystemic LPS has neuronal and sex-specific adverse effects in the mouse retina, which are counteracted by targeting the NLRP3 inflammasome and the extrinsic pathway of apoptosis. Our results highlight the need to analyse males and females in preclinical studies of inflammatory diseases affecting the central nervous system

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Section: Resultsmentioning

confidence: 99%

Retinal response to systemic inflammation differs between sexes and neurons

Rodríguez-Ramírez,

Norte-Muñoz,

Lucas-Ruiz

et al. 2024

Front. Immunol.

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“…This post mortem study is limited as it only offers one a snapshot of one time period after death; however, other investigations show that the inflammasome/ASC pathway may affect synaptic function when activated in microglia, 25 thus supporting that the inflammasome may…”

Section: Discussionmentioning

confidence: 99%

“…23 The studies show that inflammasome/ASC speck protein-mediated aggregation of tau. 24 Recently, it has been shown that inflammasome activation via NLRP3 sensor in microglia leads to synaptic loss and impairment of excitatory neurons using in vitro cell culture studies of sepsis, 25 but the role of the inflammasome pathway in synaptic loss seen in AD has not been well studied.…”

Section: Introductionmentioning

confidence: 99%

Association of region‐specific hippocampal reduction of neurogranin with inflammasome proteins in post mortem brains of Alzheimer's disease

Vontell,

Gober,

Dallmeier

et al. 2024

A&D Transl Res & Clin Interv

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INTRODUCTIONNeurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.METHODSWe investigated the protein expression, morphological differences of Ng, and correlated Ng to hyperphosphorylated tau in the post mortem brains of 17 AD cases and 17 age‐ and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC).RESULTSWe show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ASC positive microglia, in AD.DISCUSSIONThe finding of a negative correlation between Ng and ASC speck protein expression in post mortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD.Highlights We show the role that neurogranin plays on post‐synaptic signaling in specific hippocampal regions. We demonstrate that there could be clinical implications of using neurogranin as a biomarker for dementia. We describe the loss of plasticity and neuronal scaffolding proteins in the present of AD pathology. We show the response of neuroinflammation when tau proteins phosphorylate in hippocampal neurons. We show that there is a potential therapeutic target for the inflammasome, and future studies may show that IC100, a humanized monoclonal antibody directed against ASC, may slow the progression of neurodegeneration.

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“…Active caspase-1 also cleaves gasdermin D (GSDMD) and triggers pyroptosis, resulting in release of mature IL-1β ( Shi et al, 2017 ). It has been found that activated microglia, not astrocytes, are the sole source of NLRP3 inflammasome in CNS of rodents ( Gustin et al, 2015 ; Moraes et al, 2023 ). Numerous studies have demonstrated that NLRP3-induced IL-1β release is the main cause of the brain dysfunction following sepsis ( Sui et al, 2016 ; Xie et al, 2020 ; Yan et al, 2022 ).…”

Section: Activation Of Inflammasome and Release Of Il-1βmentioning

confidence: 99%

“…Numerous studies have demonstrated that NLRP3-induced IL-1β release is the main cause of the brain dysfunction following sepsis ( Sui et al, 2016 ; Xie et al, 2020 ; Yan et al, 2022 ). Pharmacological inhibition of NLRP3 not only reduces the expression of IL-1β, but also alleviates cognition impairment after sepsis ( Sui et al, 2016 ; Xie et al, 2020 ; Li et al, 2022 ; Sekino et al, 2022 ; Moraes et al, 2023 ).…”

Section: Activation Of Inflammasome and Release Of Il-1βmentioning

confidence: 99%

IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

Zhu,

Wan,

Huang

et al. 2024

Front. Neurosci.

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Sepsis is a leading cause of death resulting from an uncontrolled inflammatory response to an infectious agent. Multiple organ injuries, including brain injuries, are common in sepsis. The underlying mechanism of sepsis-associated encephalopathy (SAE), which is associated with neuroinflammation, is not yet fully understood. Recent studies suggest that the release of interleukin-1β (IL-1β) following activation of microglial cells plays a crucial role in the development of long-lasting neuroinflammation after the initial sepsis episode. This review provides a comprehensive analysis of the recent literature on the molecular signaling pathways involved in microglial cell activation and interleukin-1β release. It also explores the physiological and pathophysiological role of IL-1β in cognitive function, with a particular focus on its contribution to long-lasting neuroinflammation after sepsis. The findings from this review may assist healthcare providers in developing novel interventions against SAE.

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Microglial NLRP3 Inflammasome Induces Excitatory Synaptic Loss Through IL-1β-Enriched Microvesicle Release: Implications for Sepsis-Associated Encephalopathy

Cited by 16 publications

References 41 publications

Retinal response to systemic inflammation differs between sexes and neurons

Retinal response to systemic inflammation differs between sexes and neurons

Association of region‐specific hippocampal reduction of neurogranin with inflammasome proteins in post mortem brains of Alzheimer's disease

IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

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