Interleukin-10 Prevents Pathological Microglia Hyperactivation following Peripheral Endotoxin Challenge

Shemer, Anat; Scheyltjens, Isabelle; Frumer, Gal Ronit; Kim, Jung Seok; Grozovski, Jonathan; Ayanaw, Serkalem; Dassa, Bareket; Hove, Hannah Van; Chappell‐Maor, Louise; Boura‐Halfon, Sigalit; Leshkowitz, Dena; Mueller, Werner; Maggio, Nicola; Movahedi, Kiavash; Jung, Steffen

doi:10.1016/j.immuni.2020.09.018

Cited by 102 publications

(81 citation statements)

References 92 publications

(117 reference statements)

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“…Similar results were obtained, when RT-qPCR analysis for Tnfa -mRNA was carried out at the end of each experiment in the same set of tissue cultures ( Figure 4D ). The results demonstrate the anti-inflammatory effects of IL10 in LPS-treated tissue cultures, which is in line with recent reports ( 28 ). Thus, we conclude that tissue cultures prepared from our new TNFα-reporter mouse line are suitable tools for studying neural inflammation and anti-inflammatory intervention.…”

Section: Resultssupporting

confidence: 93%

“…In this earlier study, we showed that a high concentration of TNFα impairs the expression of excitatory synaptic plasticity, which reflects the LPS effects reported in the present study. It is conceivable, therefore, that TNFα contributed to the detrimental effects of LPS on synaptic plasticity in our experimental setting, which is supported by recent studies on microglial TNFα deficiency ( 28 ). However, the precise molecular signaling pathways and neuronal targets through which TNFα (and other pro-inflammatory cytokines) modulate synaptic plasticity, e.g.…”

Section: Discussionsupporting

confidence: 72%

“…Notably, IL10 has recently been linked to the modulation of excitatory neurotransmission (64,65), suggesting that microglia may affect synaptic plasticity via IL10. However, to date, transcriptome analyses of microglia isolated from various in vivo disease models have failed to demonstrate IL10 expression in microglia (28,(66)(67)(68). For example, recovery from spinal cord injury depended on IL10, which was produced by monocytes and not microglia (69).…”

Section: Discussionmentioning

confidence: 99%

“…While it is suspected that LPS can act directly on neuronal tissue to induce inflammation and alterations in synaptic plasticity, direct evidence for this remains scarce. Furthermore, the major source of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFa), which has been linked to synaptic plasticity modulation (24)(25)(26)(27) is not well-characterized, while recent data suggest a distinct role of microglia derived TNFa in the regulation of LTP (28). Therefore, in the present study, we employed in vitro LPS exposure of entorhino-hippocampal tissue cultures prepared from a novel TNFa-reporter mouse strain that expresses the enhanced green fluorescent protein (eGFP) under the control of the Tnfa promoter [C57BL/6-Tg (TNFa-eGFP)] to monitor LPS-induced neural inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation

et al. 2020

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Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation

et al. 2020

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“…It is conceivable that severe systemic inflammation leads to activation of cerebral immune cells, e.g. microglia thereby inducing a pathological proinflammatory milieu in the brain (9)(10)(11)(12). However, it is unclear how sepsis-induced neuroinflammation leads to severe and persistent neuronal and synaptic dysfunction resulting in neurocognitive defects.…”

Section: Introductionmentioning

confidence: 99%

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

Grünewald

Wickel

Hahn

et al. 2021

Preprint

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Sepsis-associated encephalopathy (SAE) is a major and frequent complication in patients with sepsis resulting in delirium and premature death. Sepsis survivors commonly suffer from long-term cognitive impairment causing immense burden on patients, caregivers, and economic health systems. The underlying pathophysiology of SAE is largely unresolved, thus treatment options are missing. We report that experimental polymicrobial sepsis in mice induces synaptic pathology in the central nervous system underlying defective long-term potentiation and cognitive dysfunction. Analysis of differentially expressed genes revealed severely affected downregulation of genes related to neuronal and synaptic signaling in the brain, e.g. of the activity-regulated cytoskeleton-associated protein (Arc), of the transcription-regulatory EGR family, and of the dual-specificity phosphatase 6 (Dusp6). On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain was disturbed during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by bilateral in-vivo stereotactic microinjection of an adeno-associated virus containing a neuron-specific plasmid of the Arc transgene. Hereby, defective synaptic plasticity and signaling in the hippocampus were restored and memory function improved. Accordingly, synaptic plasticity, neuronal spine pathology, and memory dysfunction also improved when post-septic mice were subjected to enriched environment demonstrating the potential for activity-induced recovery of long-term cognitive dysfunction. Together, we identified synaptic pathology of neurocognitive dysfunction after severe systemic infection and provide a proof-of-concept approach to interfere with SAE pathomechanisms leading to cognitive improvement.

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Transcriptome of microglia reveals a species‐specific expression profile in bovines with conserved and new signature genes

Tavares-Gomes

Monney

Neuhaus

et al. 2021

Glia

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Evidence is growing that microglia adopt different roles than monocyte‐derived macrophages (MDM) during CNS injury. However, knowledge about their function in the pathogenesis of neuroinfections is only rudimentary. Cattle are frequently affected by neuroinfections that are either zoonotic or related to diseases in humans, and, hence, studies of bovine neuroinfections as a natural disease model may generate fundamental data on their pathogenesis potentially translatable to humans. We investigated the transcriptomic landscape and lineage markers of bovine microglia and MDM. Although bovine microglia expressed most microglial signature genes known from humans and mice, they exhibited a species‐specific transcriptomic profile, including strikingly low expression of TMEM119 and enrichment of the two scavenger receptors MEGF10 and LY75. P2RY12 was amongst the most enriched genes in bovine microglia, and antibodies against P2RY12 labeled specifically resting microglia, but also reactive microglia within neuroinfection foci in‐situ. On the other hand, F13A1 was amongst the most enriched genes in bovine monocytes and MDM and, additionally, the encoded protein was expressed in‐situ in monocytes and MDM in the inflamed brain but not in microglia, making it a promising marker for infiltrating MDM in the brain. In culture, primary bovine microglia downregulated signature genes, expressed markers of activation, and converged their transcriptome to MDM. However, they retained several microglia signature genes that clearly distinguished them from bovine MDM, making them a promising in‐vitro tool to study mechanisms of microglia–pathogen interactions.

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Interleukin-10 Prevents Pathological Microglia Hyperactivation following Peripheral Endotoxin Challenge

Cited by 102 publications

References 92 publications

Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation

Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

Transcriptome of microglia reveals a species‐specific expression profile in bovines with conserved and new signature genes

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