Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function

He, Danyang; Xu, Heping; Zhang, Huiyuan; Tang, Rui; Lan, Yangning; Xing, Ruxiao; Li, Shaomin; Christian, Elena; Hou, Yu; Lorello, Paul J.; Caldarone, Barbara J.; Ding, Jiarui; Nguyễn, Lan; Dionne, Danielle; Thakore, Pratiksha I.; Schnell, Alexandra; Huh, Jun R.; Rozenblatt-Rosen, Orit; Regev, Aviv; Kuchroo, Vijay K.

doi:10.1016/j.immuni.2021.12.001

Cited by 71 publications

(48 citation statements)

References 66 publications

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“…A recent study also documented that the CNS protection provided by IL-33 is primarily due to its ability to induce IL-10 production in microglia, whereas genetic deletion of ST2 expanded cerebral infarction by switching microglia toward an M1-like phenotype [ 29 ]. Genetic perturbation of IL-33 causes microglial impairment, synaptic dysfunction, and behavioral deficits by damaging the microglia–astrocyte circuit [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke

Deng

Wang

Zhang

et al. 2022

Cells

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This paper aimed to explore the roles of the combination of electroacupuncture (EA) and induced pluripotent stem cell-derived small extracellular vesicles (iPSC-EVs) on mice with ischemic stroke and the underlying mechanisms. A focal cerebral ischemia model was established in C57BL/6 mice through middle cerebral artery occlusion (MCAO). After 3 days, neurological impairment and motor function were examined by performing behavioral tests. The infarct volume and neuronal apoptosis were examined using TTC staining and TUNEL assays. Flow cytometry was performed to assess the proliferation of T lymphocytes. The changes in the interleukin (IL)-33/ST2 axis were evaluated by immunofluorescence and Western blotting. The combination of EA and iPSC-EVs treatment ameliorated neurological impairments and reduced the infarct volume and neuronal apoptosis in MCAO mice. EA plus iPSC-EVs suppressed T helper (Th1) and Th17 responses and promoted the regulatory T cell (Treg) response. In addition, EA plus iPSC-EVs exerted neuroprotective effects by regulating the IL-33/ST2 axis and inhibiting the microglia and astrocyte activation. Taken together, the study shows that EA and iPSC-EVs exerted a synergistic neuroprotective effect in MCAO mice, and this treatment may represent a novel potent therapy for ischemic stroke and damage to other tissues.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke

Deng

Wang

Zhang

et al. 2022

Cells

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“…We found that Piezo1 knock-down significantly decreased FAM-fAβ42 uptake in primary microglia cells (Figures 4F-4G). In addition, fAβ42 induced cellular surface enlargement with the formation of filopodia-like structures that have been proven to facilitate phagocytosis (He et al, 2022; Kress et al, 2007) was dramatically abrogated due to Piezo1 knock-down in primary microglia cultured on the soft hydrogel (Figures S5F-S5G). Therefore, these data illustrate that Piezo1 plays an essential role in modulating microglial phagocytic activity via stiffness sensing, which is able to contribute to the augmentation of Aβ deposition caused by microglial Piezo1 deficiency in the brain of 5×FAD mice.…”

Section: Resultsmentioning

confidence: 99%

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Jin

Zhu

Yang

et al. 2022

Preprint

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SummaryThe pathology of Alzheimer’s disease (AD) is associated with the extracellular amyloid-β (Aβ) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of Aβ fibrils. The upregulation of Piezo1 in Aβ plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of Aβ plaques, resulting in the exacerbation of Aβ and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain Aβ burden and cognitive impairment in the 5×FAD mouse. Together, our results reveal Piezo1, as a mechanosensor of Aβ fibrils stiffness in microglia, could represent a promising therapeutic target for AD.

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“…PTEN or SHIP-1 negatively regulates microglial phagocytosis and energy metabolism by inhibiting AKT activation. Inhibition of mitochondria-dependent energy metabolism reduces the ability of microglia to phagocytic synaptosomes (He et al, 2022 ).…”

Section: Il-33/st2mentioning

confidence: 99%

Regulation of microglia phagocytosis and potential involvement of exercise

Wang

Xing

et al. 2022

Front. Cell. Neurosci.

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Microglia are considered the main phagocytic cells in the central nervous system, remodeling neural circuits by pruning synapses during development. Microglial phagocytosis is also a crucial process in maintaining adult brain homeostasis and clearing potential toxic factors, which are recognized to be associated with neurodegenerative and neuroinflammatory disorders. For example, microglia can engulf amyloid-β plaques, myelin debris, apoptotic cells, and extracellular harmful substances by expressing a variety of specific receptors on the cell surface or by reprogramming intracellular glucose and lipid metabolism processes. Furthermore, physical exercise has been implicated to be one of the non-pharmaceutical treatments for various nervous system diseases, which is closely related to neuroplasticity and microglia functions including proliferation, activation, and phagocytosis. This review focuses on the central regulatory mechanisms related to microglia phagocytosis and the potential role of exercise training in this process.

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Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function

Cited by 71 publications

References 66 publications

Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke

Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Regulation of microglia phagocytosis and potential involvement of exercise

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