Aged lipid‐laden microglia display impaired responses to stroke

Arbaizar-Rovirosa, Maria; Pedragosa, Jordi; Lozano, Juan José; Casal, Carme; Pol, Albert; Gallizioli, Mattia; Planas, Anna M.

doi:10.15252/emmm.202217175

Cited by 36 publications

(32 citation statements)

References 76 publications

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“…Aged microglia accumulate LDs and adopt a pro-inflammatory state (Marschallinger et al, 2020). The presence of these lipid-laden microglia correlates with an impaired response to stroke in aged mice (Arbaizar-Rovirosa et al 2023). Although it remains to be determined whether APOE can traffic to LDs in microglia, we speculate that LD-associated APOE4 in microglia could also play a key role in AD pathology.…”

Section: Discussionmentioning

confidence: 87%

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

Windham

Ragusa

Wallace

et al. 2023

Preprint

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The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to neutral lipid synthesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the ER lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs containing more unsaturated triglyceride. This LD size distribution phenotype was rescued by chimeric APOE that targets only LDs. APOE4-expressing astrocytes also form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the larger LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer's disease risk.

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Section: Discussionmentioning

confidence: 87%

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

Windham

Ragusa

Wallace

et al. 2023

Preprint

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“…The accumulation of d-LDs is exacerbated in the microglia of old individuals driving an exaggerated type I IFN immune response and worsening the neurological outcome. 159 Hence, the equilibrium between f-and d-LDs could be somehow disrupted in unhealthy cells and contribute to pathogenesis.…”

Section: Toxoplasma Gondimentioning

confidence: 99%

“…157,158 For example, we have recently observed that after brain ischemia LDs accumulate in microglia, a population of immune cells residing in the brain. 159 These LDs resemble d-LDs and contain ISGs such as viperin, ISG15, RNF213, IFI47, TGTP1, IIGP1, and GBP6. After a stroke in elderly patients, the accumulation of d-LDs is exacerbated with a concomitantly aggravated type I IFN immune response that worsened the neurological outcome.…”

Section: Box 6 Interferons In Innate Immunitymentioning

confidence: 99%

“…However, LDs accumulating in pathological conditions such as obesity, cancer, or aging are, like d‐LDs, associated with inflammation and cell damage 157,158 . For example, we have recently observed that after brain ischemia LDs accumulate in microglia, a population of immune cells residing in the brain 159 . These LDs resemble d‐LDs and contain ISGs such as viperin, ISG15, RNF213, IFI47, TGTP1, IIGP1, and GBP6.…”

Section: Concluding Remarks Open Questions and Future Directionsmentioning

confidence: 99%

“…These LDs resemble d‐LDs and contain ISGs such as viperin, ISG15, RNF213, IFI47, TGTP1, IIGP1, and GBP6. After a stroke in elderly patients, the accumulation of d‐LDs is exacerbated with a concomitantly aggravated type I IFN immune response that worsened the neurological outcome 159 . Hence, the equilibrium between f‐ and d‐LDs could be disrupted and promote disease.…”

Section: Concluding Remarks Open Questions and Future Directionsmentioning

confidence: 99%

See 2 more Smart Citations

Defensive‐lipid droplets: Cellular organelles designed for antimicrobial immunity

Safi

Sánchez-Álvarez

Bosch

et al. 2023

Immunological Reviews

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SummaryMicrobes have developed many strategies to subvert host organisms, which, in turn, evolved several innate immune responses. As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders. Intracellular viruses, bacteria, and protozoan parasites induce and physically interact with LDs, and the current view is that they “hijack” LDs to draw on substrates for host colonization. This dogma has been challenged by the recent demonstration that LDs are endowed with a protein‐mediated antibiotic activity, which is upregulated in response to danger signals and sepsis. Dependence on host nutrients could be a generic “Achilles’ heel” of intracellular pathogens and LDs a suitable chokepoint harnessed by innate immunity to organize a front‐line defense. Here, we will provide a brief overview of the state of the conflict and discuss potential mechanisms driving the formation of the ‘defensive‐LDs’ functioning as hubs of innate immunity.

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Macrophage and monocyte subsets in response to ischemic stroke

Blank‐Stein,

Mass

2023

Eur J Immunol

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Ischemic stroke is a leading cause of disability and mortality. Despite extensive efforts in stroke research, the only pharmacological treatment currently available is arterial recanalization, which has limited efficacy only in the acute phase of stroke. The neuroinflammatory response to stroke is believed to provide a wider time window than recanalization and has therefore been proposed as an attractive therapeutic target. In this review, we provide an overview of recent advances in the understanding of cellular and molecular responses of distinct macrophage populations following stroke, which may offer potential targets for therapeutic interventions. Specifically, we discuss the role of local responders in neuroinflammation, including the well‐studied microglia as well as the emerging players, border‐associated macrophages, and macrophages originating from the skull bone marrow. Additionally, we focus on the behavior of monocytes stemming from distant tissues, such as the bone marrow and spleen. Finally, we highlight aging as a crucial factor modulating the immune response, which is often neglected in animal studies.This article is protected by copyright. All rights reserved

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Aged lipid‐laden microglia display impaired responses to stroke

Cited by 36 publications

References 76 publications

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

Defensive‐lipid droplets: Cellular organelles designed for antimicrobial immunity

Macrophage and monocyte subsets in response to ischemic stroke

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