Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification

Lööv, Camilla; Mitchell, Claire H.; Simonsson, Martin; Erlandsson, Anna

doi:10.1002/glia.22873

Cited by 44 publications

(30 citation statements)

References 69 publications

(93 reference statements)

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“…A general slow digestion in astrocytes may be explained by their antigen presentation properties. Several studies have suggested that astrocytes are involved in T-cell activation because they express major histocompatibility complex class II ( Cornet et al, 2000 ; Lööv et al, 2015 ). Accordingly, T-cell infiltration has been observed in the PD brain at advanced disease stages.…”

Section: Discussionmentioning

confidence: 99%

Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes

et al. 2017

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Many lines of evidence suggest that the Parkinson's disease (PD)-related protein α-synuclein (α-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.SIGNIFICANCE STATEMENT Astrocytes are the major cell type in the brain, yet their role in Parkinson's disease progression remains elusive. Here, we show that human astrocytes actively transfer aggregated α-synuclein (α-SYN) to healthy astrocytes via direct contact and tunneling nanotubes (TNTs), rather than degrade it. The astrocytes engulf large amounts of oligomeric α-SYN that are subsequently stored in the trans-Golgi network region. The accumulation of α-SYN in the astrocytes affects their lysosomal machinery and induces mitochondrial damage. The stressed astrocytes respond by sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes. Our findings highlight an unexpected role of astrocytes in the propagation of α-SYN pathology via TNTs, revealing astrocytes as a potential target for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes

et al. 2017

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“…37,38 Phagocytosis is mediated by both professional and non-professional phagocytic cells including macrophages, dendritic cells, tissue-infiltrating monocytes, neutrophils, and eosinophils as well as epithelial cells of mammary epithelium and astrocytes in the brain. [38][39][40] However, in the majority of cases, phagocytic clearance is primarily undertaken by macrophages. 37 This is likely the case in the context of hematopoietic engulfment of chondrocytes during fracture repair, since we show macrophages are present at the Transition Zone.…”

Section: Discussionmentioning

confidence: 99%

β-catenin Signaling Regulates Cell Fate Decisions at the Transition Zone of the Chondro-Osseous Junction During Fracture Healing

Wong

Shao

et al. 2020

Preprint

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Chondrocytes within the fracture callus transform into osteoblasts during bone regeneration, but the molecular mechanisms regulating this process are unknown. Wnt ligands are expressed within the fracture callus, and hypertrophic chondrocytes undergoing transformation to osteoblasts exhibit nuclear localization of β-catenin, indicating active Wnt signaling in these cells. Here, we show that conditional knock out (cKO) of β-catenin in chondrocytes inhibits the transformation of chondrocytes to osteoblasts, while stabilization of β-catenin in chondrocytes accelerates this process. After cKO, chondrocyte-derived cells were located in the bone marrow cavity and upon re-fracture formed cartilage. Lineage tracing in wild type mice revealed that in addition to osteoblasts, chondrocytes give rise to stem cells that contribute to repair of subsequent fractures. These data indicate that Wnt signaling directs cell fate choices of chondrocytes during fracture healing by stimulating transformation of chondrocytes to osteoblasts, and provide a framework for developing Wnt-therapies to stimulate repair.

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“…Professional phagocytes are composed of macrophages, immature dendritic cells (DCs), tissue-infiltrating monocytes, neutrophils, and eosinophils. Non-professional phagocytes in the lung consist predominantly of epithelial cells but include cells such as connective tissue cells, muscle cells and endothelial cells [101,102]. Removing cell debris and eliminating cells undergoing programmed cell death are crucial processes in containing ongoing inflammation and the resolution of inflammation [103,104].…”

Section: Phagocytosis Of Lmsmentioning

confidence: 99%

Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease

Akata

Eeden

2020

IJMS

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Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD.

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Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification

Cited by 44 publications

References 69 publications

Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes

Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes

β-catenin Signaling Regulates Cell Fate Decisions at the Transition Zone of the Chondro-Osseous Junction During Fracture Healing

Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease

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