Microglia-dependent synapse loss in type I interferon-mediated lupus

Bialas, Allison R.; Présumey, Jessy; Das, Abhishek; Poel, Cees E. van der; Lapchak, Peter H.; Mesin, Luka; Victora, Gabriel D.; Tsokos, George C.; Mawrin, Christian; Herbst, Ronald; Carroll, Michael

doi:10.1038/nature22821

Cited by 166 publications

(163 citation statements)

References 38 publications

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“…Upregulation of CD68 immunoreactivity indicates enhanced phagocytic activity in microglia and can be related to increased synapse engulfment [16, 28]. In the current study, we showed a linear relationship between loss of synaptic proteins and CD68 immunoreactivity, suggesting orthopedic surgery increases microglial phagocytosis of hippocampal synapses.…”

Section: Discussionsupporting

confidence: 61%

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Complement activation contributes to perioperative neurocognitive disorders in mice

Xiong

Lü

Lin

et al. 2018

J Neuroinflammation

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BackgroundThe complement system plays an important role in many neurological disorders.Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND.MethodsA stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker.ResultsC3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function.ConclusionsOrthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1292-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 61%

“…Notably, upregulation of microglial phagocytic activity has been related to increased synapse engulfment [16, 20, 28]. Here, we showed a significant correlation between microglial CD68 expression and synapse numbers (SYP: r = − 0.606, p = 0.017, Fig.…”

Section: Resultssupporting

confidence: 51%

Complement activation contributes to perioperative neurocognitive disorders in mice

Xiong

Lü

Lin

et al. 2018

J Neuroinflammation

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“…This is also supported by IPA that showed that a number of genes expressed in astrocytes and microglia are known to contribute to neurological diseases. Further, the common IFN-I response in treated microglia shows some functional similarities (such as genes required for sensing endogenous molecules and pathogens) to recently reported changes in gene expression in microglia from a mouse model of CNS lupus (Bialas et al, 2017), an IFN-a-associated disease. Further, the common IFN-I response in treated microglia shows some functional similarities (such as genes required for sensing endogenous molecules and pathogens) to recently reported changes in gene expression in microglia from a mouse model of CNS lupus (Bialas et al, 2017), an IFN-a-associated disease.…”

Section: Color Online and Bw In Printsupporting

confidence: 61%

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Wen

Viengkhou

Denyer

et al. 2018

Glia

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Type I interferons (IFN-I) are crucial for effective antimicrobial defense in the central nervous system (CNS) but also can cause severe neurological disease (termed cerebral interferonopathy) as exemplified by Aicardi-Goutières Syndrome. In the CNS, microglia and astrocytes have essential roles in host responses to infection and injury, with both cell types responding to IFN-I. While the IFN-I signaling pathways are the same in astrocytes and microglia, the extent to which the IFN-I responses of these cells differ, if at all, is unknown. Here we determined the global transcriptional responses of astrocytes and microglia to the IFN-I, IFN-α. We found that under basal conditions, each cell type has a unique gene expression pattern reflective of its developmental origin and biological function. Following stimulation with IFN-α, astrocytes and microglia also displayed a common core response that was characterized by the increased expression of genes required for pathogen detection and elimination. Compared with astrocytes, microglia had a more extensive and diverse response to IFN-α with significantly more genes with expression upregulated (282 vs. 141) and downregulated (81 vs. 3). Further validation was documented for selected IFN-I-regulated genes in a murine model of cerebral interferonopathy. In all, the findings highlight not only overlapping but importantly divergent responses to IFN-I by astrocytes versus microglia. This suggests specialized roles for these cells in host defense and in the development of cerebral interferonopathy.

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“…These mice develop characteristic signs of SLE, due to the production of polyreactive autoantibodies against ssDNA, RNA, and nucleosomes, and activation of the IFN‐I response (Berland et al, ; Das et al, ; Han et al, ). They also show significant neurological deficits, with poor performance in cognitive and behavioral tasks, which are rescued by treatment with anti‐IFNAR antibody (Bialas et al, ). The 564Igi mice show an IFN‐I‐dependent increase in the number of reactive microglia in the CNS (Bialas et al, ).…”

Section: The Response Of Microglia In Il‐6‐ and Ifn‐i‐mediated Neuroimentioning

confidence: 99%

“…They also show significant neurological deficits, with poor performance in cognitive and behavioral tasks, which are rescued by treatment with anti‐IFNAR antibody (Bialas et al, ). The 564Igi mice show an IFN‐I‐dependent increase in the number of reactive microglia in the CNS (Bialas et al, ). Microglia also phagocytose neuronal synapse material in an IFN‐I‐dependent manner, contributing to the reduction of synaptic density in the frontal cortex of the 564Igi mice (Bialas et al, ).…”

Section: The Response Of Microglia In Il‐6‐ and Ifn‐i‐mediated Neuroimentioning

confidence: 99%

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

West

Viengkhou

Campbell

et al. 2019

Glia

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Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin‐6 (IL‐6) and members of the type I interferon (IFN‐I) family, IFN‐alpha (IFN‐α), and IFN‐beta (IFN‐β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed “cerebral cytokinopathies.” IL‐6 and IFN‐α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi‐Goutières syndrome, respectively, whereas IFN‐β has an emerging role as a causal factor in age‐associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL‐6 and IFN‐I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL‐6 and IFN‐I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL‐6 or IFN‐I.

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Microglia-dependent synapse loss in type I interferon-mediated lupus

Cited by 166 publications

References 38 publications

Complement activation contributes to perioperative neurocognitive disorders in mice

Complement activation contributes to perioperative neurocognitive disorders in mice

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

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