Neurotoxic reactive astrocytes are induced by activated microglia

Liddelow, Shane A.; Guttenplan, Kevin A.; Clarke, Laura; Bennett, F. Chris; Bohlen, Christopher J.; Schirmer, Lucas; Bennett, Mariko L.; Münch, Alexandra E.; Chung, Won‐Suk; Peterson, Todd C.; Wilton, Daniel K.; Frouin, Arnaud; Napier, Brooke A.; Panicker, Nikhil; Kumar, Manoj; Buckwalter, Marion S.; Rowitch, David H.; Dawson, Valina L.; Dawson, Ted M.; Stevens, Beth; Barres, Ben A.

doi:10.1038/nature21029

Cited by 5,766 publications

(7,139 citation statements)

References 48 publications

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“…Higher levels of proinflammatory cytokines were found in brain regions that also showed lower TSPO expression as measured using immunohistochemistry (55), an observation that paralleled TSPO PET and cerebrospinal fluid data in patients (24). Importantly, microglia and astrocytes have been found to exist in both pro-and antiinflammatory states (56,57), which cannot be differentiated by TSPO. Indeed, very recent in vitro data suggest that M1…”

Section: Meta-analysis Of Tspo In Patients With Psychosismentioning

confidence: 74%

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Plavén-Sigray

Matheson

Collste

et al. 2018

Biological Psychiatry

110

102

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BACKGROUND: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects. METHODS: PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (V T ), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients' TSPO levels compared with healthy control subjects. RESULTS: Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower V T in patients relative to no difference (all BFs .

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Section: Meta-analysis Of Tspo In Patients With Psychosismentioning

confidence: 74%

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Plavén-Sigray

Matheson

Collste

et al. 2018

Biological Psychiatry

110

102

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“…Two recent studies have demonstrated that TNFα contributes to the induction of neurotoxic astrocytes. Liddelow et al (2017) have reported that TNFα, in combination with cytokines Il‐1α and C1q, produces a reactive and neurotoxic phenotype characterized by loss of supportive functions and the release of soluble toxic factor(s). Additionally, Almad et al (2016) have recently shown that soluble TNFα acts on astrocytes to enhance Cx43 hemichannel function.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

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“…Importantly, GFAP was not different between NL2 cHET and cKO astrocytes (Extended Data Fig. 9e), indicating that NL2 cKO cells retained their astrocyte identity and did not undergo pathological reactivation characterized by enhanced GFAP expression 6,31 . Genotyping the sorted cells using allele-specific primers verified the recombination of the NL2 locus (Extended Data Fig.…”

Section: Astrocytic Nl2 Controls Synapse Functionmentioning

confidence: 93%

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

Stogsdill

Ramirez

Liu

et al. 2017

Nature

396

413

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Astrocytes are highly complex glial cells with numerous fine cellular processes which infiltrate the neuropil to interact with synapses. The mechanisms controlling the establishment of astrocytes’ remarkable morphology and how impairing astrocytic infiltration of the neuropil alters synaptic connectivity are largely unknown. Here we find that cortical astrocyte morphogenesis depends on direct contact with neuronal processes and occurs in tune with the growth and activity of synaptic circuits. Neuroligin (NL) family cell adhesion proteins, NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, cortical excitatory synapse formation and function is diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a novel mechanism of action for NLs and link astrocyte morphogenesis to synaptogenesis. Because NL mutations are implicated in various neurological disorders, these findings also offer an astrocyte-based mechanism of neural pathology.

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Neurotoxic reactive astrocytes are induced by activated microglia

Cited by 5,766 publications

References 48 publications

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

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