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Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, Taloma SE, Barron JJ, Molofsky AB, Kheirbek MA, Molofsky AV. Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell. 2020 Jul 23;182(2):388-403.e15. Epub 2020 Jul 1 PubMed.
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Hong Kong University of Science & Technology
As an alarmin, interleukin-33 (IL-33) is expressed and secreted by neural cells, including astrocytes and oligodendrocytes, to maintain tissue homeostasis (Liew et al., 2016). In this study, Nguyen et al reports an unexpected role of neuronal IL-33 in synapse remodelling in the hippocampus and memory consolidation. They show that experience-dependent increase of IL-33 from a neuronal subpopulation enhances structural synapse formation, and promotes synaptic plasticity through a microglial-dependent engulfment of extracellular matrix.
The authors demonstrate that IL-33 is expressed in a neuronal subpopulation in the dentate gyrus and that its secretion is regulated by experience. They further show that the secreted IL-33 regulates experience-dependent synaptic remodeling by modulating microglial clearance of the extracellular matrix. Whereas the IL-33-dependent neuron/microglial signaling is required for remote memory precision, the IL-33 expression in the hippocampus decreases upon aging and is associated with impaired memory precision. Their work clearly delineates how IL-33 is regulated in a subset of hippocampal neurons by experience and its role in promoting synapse formation through activation of microglial phagocytosis.
Interestingly, our unpublished observation also shows that IL-33 release in the hippocampal CA1 region is regulated by experience, pointing toward a role of astrocytic IL-33 in CA1 synaptic plasticity. Therefore, it is likely that IL-33 is released from distinct neural cell types to enhance synapse formation in specific neural circuits in response to experience.
The authors further show that the proportion of IL-33-positive neurons decreases in aged mice and is associated with reduced spine density. While it is unclear why neuronal IL-33 decreases with aging, this data supports the notion that impaired IL-33/ST2 signaling contributes to age-related cognitive decline. Indeed, this idea is in line with previous reports that reduced transcript level of IL-33 in Alzheimer’s disease brain (Chapuis et al., 2009) and increased level of IL-33 decoy receptor sST2 in the serum of patients with mild cognitive impairment (Fu et al., 2016) is associated with Alzheimer’s disease progression. Therefore, it is intriguing to speculate that decreased IL-33/ST2 signaling is the key driver of hippocampal synaptic dysfunction in Alzheimer’s disease. Of note, we have previously demonstrated that replenishing IL-33 can improve the impaired hippocampal synaptic plasticity in an Aβ-deposition transgenic mouse model (Fu et al., 2016). It would be of great interest to investigate whether IL-33 directly regulates hippocampal synaptic remodeling in Alzheimer’s disease.
Here, the authors have shown that IL-33 is necessary and sufficient for the microglial phagocytosis and clearance of the extracellular matrix. Thus, this finding has further expanded the repertoire of IL-33-induced microglial functions in addition to phagocytosis of Aβ plaques (Fu et al., 2016; Lau et al., 2020), restraining CNS injury (Gadani et al., 2015), and synaptic pruning (Vainchtein et al., 2018).
Our recent study shows that IL-33 administration induces a microglial subpopulation, termed IL-33-responsive microglia (IL-33RM) (Lau et al., 2020); these microglia are MHC-II+ with enhanced phagocytosis and clearance capacity. Moreover, IL-33 induces the state transition and functional modulation of microglia through regulation of their epigenetic landscape, including chromatin accessibility and PU.1 binding. Hence, it would be of interest to examine whether similar regulatory control of the microglial state transition occurs in hippocampal synaptic plasticity in health and Alzheimer’s disease. Given that PU.1 can interact with various transcription factors in transcriptome regulation (Glass and Natoli, 2016; Heinz et al., 2010), understanding how PU.1 transcription factor complexes control microglial state transition might provide insight into the molecular control of microglial dysfunction in Alzheimer’s disease.
References:
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Vainchtein ID, Chin G, Cho FS, Kelley KW, Miller JG, Chien EC, Liddelow SA, Nguyen PT, Nakao-Inoue H, Dorman LC, Akil O, Joshita S, Barres BA, Paz JT, Molofsky AB, Molofsky AV. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science. 2018 Mar 16;359(6381):1269-1273. Epub 2018 Feb 1 PubMed.
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