Endoplasmic reticulum stress is transmissible <i>in vitro</i> between cells of the central nervous system

Sprenkle, Neil T.; Lahiri, Anirudhya; Simpkins, James W.; Meares, Gordon P.

doi:10.1111/jnc.14642

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…S1b,e and S2b) as well as acceptor cells (Fig. S1c,f and S2c), reproducing the published results obtained using tumor cells and macrophages (Mahadevan et al ) and neuronal cells (Sprenkle et al, ). However, whereas UPR activation increased over time in donor cells, the CM‐induced UPR activation in acceptor cells at 1 h reached maximum levels and did not show this increase at subsequent time points (Fig.…”

Section: Resultssupporting

confidence: 90%

“…Transmission of full UPR signaling, that is, activation of all three branches of the UPR, has been reported in cell models using transfer of conditioned media (CM) of tumor cells subjected to ER stress, to unstressed macrophages (Mahadevan et al ). A similar model in neuronal cells and astrocytes also showed transmission of the signaling by all UPR branches (Sprenkle et al, ). In agreement with the danger signaling hypothesis, CM treatment resulted in resistance to subsequent ER stress in these cell‐to‐cell transmission models (Rodvold et al ; Sprenkle et al, ).…”

mentioning

confidence: 82%

“…A similar model in neuronal cells and astrocytes also showed transmission of the signaling by all UPR branches (Sprenkle et al, ). In agreement with the danger signaling hypothesis, CM treatment resulted in resistance to subsequent ER stress in these cell‐to‐cell transmission models (Rodvold et al ; Sprenkle et al, ).…”

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confidence: 82%

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No evidence for cell‐to‐cell transmission of the unfolded protein response in cell culture

Ziel

Wolzak

Nölle

et al. 2019

Journal of Neurochemistry

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The unfolded protein response (UPR) is one of the major cellautonomous proteostatic stress responses. The UPR has been implicated in the pathogenesis of neurodegenerative diseases and is therefore actively investigated as therapeutic target. In this respect, cell non-autonomous effects of the UPR including the reported cell-to-cell transmission of UPR activity may be highly important. A pharmaca-based UPR induction was employed to generate conditioned media (CM) from CMdonating neuronal ('donor') cells (SK-N-SH and primary mouse neurons). As previously reported, upon subsequent transfer of CM to naive neuronal 'acceptor' cells, we confirmed UPR target mRNA and protein expression by qPCR and automated microscopy. However, UPR target gene expression was also induced in the absence of donor cells, indicating carry-over of pharmaca. Genetic induction of single pathways of the UPR in donor cells did not result in UPR transmission to acceptor cells. Moreover, no transmission was detected upon full UPR activation by nutrient deprivation or inducible expression of the heavy chain of immunoglobulin M in donor HeLa cells. In addition, in direct co-culture of donor cells expressing the immunoglobulin M heavy chain and fluorescent UPR reporter acceptor HeLa cells, UPR transmission was not observed. In conclusion, carry-over of pharmaca is a major confounding factor in pharmaca-based UPR transmission protocols that are therefore unsuitable to study cell-to-cell UPR transmission. In addition, the absence of UPR transmission in non-pharmaca-based models of UPR activation indicates that cell-to-cell UPR transmission does not occur in cell culture.

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Section: Resultssupporting

confidence: 90%

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confidence: 82%

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No evidence for cell‐to‐cell transmission of the unfolded protein response in cell culture

Ziel

Wolzak

Nölle

et al. 2019

Journal of Neurochemistry

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“…For instance, Zhang et al [10] demonstrated that the ER stress present in infected cardiomyocytes was able to transmit both the ER stress and pro-inflammatory properties into macrophages via soluble molecules but cell-cell contacts were not involved. In addition, ER stress can be transmitted between astrocytes, neurons, and microglia through soluble molecules in culture conditions [116]. It is known that ROS compounds and inflammatory mediators, e.g., IL-1β, TNF-α, and HMGB1, are able to induce ER stress in several nonimmune cells [117][118][119].…”

Section: Inflamed Microenvironment Provokes Immunosuppressionmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

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The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

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“…Different studies suggested that the activation of all three branches of the UPR is transmissible from tumor cells (donors) in which ER stress was induced by using compounds to unstressed macrophages (acceptors) via conditioned media (CM) [ 70 ]. These results have been replicated in an additional tumor cell line combined with macrophages [ 71 ] and also in other cell types, including hepatocytic donor cells and macrophages [ 72 ] and neuronal cells and glia cells [ 73 ], all using a similar protocol. However, data from our group demonstrate that this compound-based UPR transmission protocol [ 70 , 71 , 72 , 73 ] is not suitable to study UPR transmission [ 50 ].…”

Section: Cell Non-autonomous Upr Signalingmentioning

confidence: 76%

The UPR in Neurodegenerative Disease: Not Just an Inside Job

Ziel

Scheper

2020

Biomolecules

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Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is illustrated by neurodegenerative disorders where disturbed neuronal proteostasis causes neuronal dysfunction and loss. For their unique function, neurons require regulated and long-distance transport of membrane-bound cargo and organelles. This highlights the importance of protein quality control in the neuronal endomembrane system, to which the unfolded protein response (UPR) is instrumental. The UPR is a highly conserved stress response that is present in all eukaryotes. However, recent studies demonstrate the existence of cell-type-specific aspects of the UPR, as well as cell non-autonomous UPR signaling. Here we discuss these novel insights in view of the complex cellular architecture of the brain and the implications for neurodegenerative diseases.

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Endoplasmic reticulum stress is transmissible in vitro between cells of the central nervous system

Cited by 22 publications

References 42 publications

No evidence for cell‐to‐cell transmission of the unfolded protein response in cell culture

No evidence for cell‐to‐cell transmission of the unfolded protein response in cell culture

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

The UPR in Neurodegenerative Disease: Not Just an Inside Job

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