Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development

Vainchtein, Ilia D.; Chin, Gregory T.; Cho, Frances S.; Kelley, Kevin W.; Miller, John G.; Chien, Elliott C.; Liddelow, Shane A.; Nguyen, Phi T.; Nakao-Inoue, Hiromi; Dorman, Leah C.; Akil, Omar; Joshita, Satoru; Barres, Ben A.; Paz, Jeanne T.; Molofsky, Ari B.; Molofsky, Anna V.

doi:10.1126/science.aal3589

Cited by 431 publications

(365 citation statements)

References 48 publications

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“…Furthermore, ST2 was found to be predominantly expressed in oligodendrocytes in MS patient brains (Allan et al, ). Most recently, using flow cytometry, cerebral ST2 was shown to be abundantly expressed in the microglia and astrocytes, but not in oligodendrocytes (Yang et al, ), while another study demonstrated most of its expression in microglia of the spinal cord (Vainchtein et al, ). In the current study, our double IF staining results showed that ST2 was mainly distributed and increased in astrocytes in the spinal cord of ACD mice.…”

Section: Discussionmentioning

confidence: 99%

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Yang

et al. 2019

Glia

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Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

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Section: Discussionmentioning

confidence: 99%

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Yang

et al. 2019

Glia

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“…Importantly, next to instructive functions of microglia towards astrocytes, astrocytes can direct microglial functioning as well. Astrocyte‐derived factors regulate microglial activation (M. Jo et al, ; Norden, Fenn, Dugan, & Godbout, ; Rocha, Cristovão, Campos, Fonseca, & Baltazar, ), phagocytosis (Jeon et al, ), and promote microglial synapse engulfment (Vainchtein et al, ). Astrocytes also actively phagocytose synapses themselves (Chung et al, ).…”

Section: Astrocytes Integrate Signals From the Environmentmentioning

confidence: 99%

The involvement of astrocytes in early‐life adversity induced programming of the brain

Abbink

Deijk

Heine

et al. 2019

Glia

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Early‐life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early‐life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes.

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“…Furthermore, microglia participate in synaptogenesis by producing neurotrophic substances, such as BDNF, as well as eliminating excessive presynaptic and postsynaptic elements through synaptic pruning via the activation of the complement pathway (Masuda & Prinz, ; Sominsky, De Luca, & Spencer, ; Stevens et al, ; Um, ). In addition to the complement‐mediated mechanism, astrocyte‐derived interleukin (IL)‐33 is also physiologically required to maintain synapse homeostasis by modulating microglial synapse engulfment (Vainchtein et al, ). Microglia are involved in regulating and shaping both excitatory and inhibitory synapses, such as γ‐aminobutyric acid‐expressing and glycinergic synapses (Cantaut‐Belarif et al, ; Um, ).…”

Section: Multi‐tasking Microglia: a Friend For Brain Homeostasismentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development

Cited by 431 publications

References 48 publications

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

The involvement of astrocytes in early‐life adversity induced programming of the brain

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

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