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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  1. The study by Vainchtein et al. emphasizes the roles of glial cells in synapse refinement during neuronal circuit development. While the involvement of microglia in synaptic engulfment in postnatal development and neurological diseases is well established, how the actions of the microglia are triggered during the process remains unclear. This study shows that Interleukin-33 (IL-33), a cellular alarmin that is important for tissue homeostasis, is released from the synapse-associated astrocytes and mediates synapse refinement in the spinal cord and the thalamus by facilitating the microglial engulfment of synapses. These findings provide us with some clues on the possible coordinated interplay of astrocytes, microglia, and neurons during the refinement of the synaptic connectivity.

    Synaptic loss is highly associated with memory decline in AD and is an early hallmark of the disease. Interestingly, our previous findings showed that IL-33 injection restored the synaptic plasticity deficit and reduced AD-like pathology in AD-transgenic mouse models through the modulation of microglial phenotypes (Fu et al., 2016). In our study, we demonstrated that IL-33 skewed the microglia toward an alternative activation state with an enhanced Aβ phagocytic ability in AD. Thus, it is interesting to speculate that IL-33 clears the unwanted materials through the activation of microglia during neural development and in the disease state. Together with the recent identification of a new microglial subtype known as disease-associated microglia (DAM) in AD transgenic mouse model, and the discovery of the change in proportion of different microglial subtypes during the progression of AD (Keren-Shaul et al., 2017), it is expected that the roles of microglia in AD are quite complicated.

    Current understanding of the roles of microglia in AD is diverse and controversial. They are involved in the engulfment of synapses, phagocytic uptake of Aβ, as well as the regulation of the inflammatory status. To have a better understanding of the crosstalk between glial cells and neurons in AD, it is critical to identify the regulation of different subtypes of microglia and evaluate their functions during the progression of AD and after IL-33 treatment. While microglia and innate immune-associated pathways are suggested to mediate the early synaptic loss in this disease (Hong et al., 2016), it will be of great interest to examine the exact roles of IL-33/ST2 in the regulation of synapse dysfunctions in AD, and investigate the involvement of different glial cell types and their coordination during the process.

    It will also be of interest to study the cellular mechanisms that underlie the action of IL-33 in synaptic refinement. This study reports that there is a decrease of gene candidates, including different chemokine members such as Cxcl1, Cxcl10, and Cxcl2, in the microglia of IL-33-/- mice. Indeed, reduction of chemokines is also observed at the injury sites in IL-33-/- mice after spinal cord injury, which is associated with reduced recruitment of monocytes and impaired recovery (Gadani et al., 2015). Thus, it is worth examining whether the action of IL-33 on the microglial-mediated functioning during development and at the injury state is via the regulation of chemokines in the microglia.

    References:

    Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, Ip NY. IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline. Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2705-13. Epub 2016 Apr 18 PubMed.

    Gadani SP, Walsh JT, Smirnov I, Zheng J, Kipnis J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron. 2015 Feb 18;85(4):703-9. Epub 2015 Feb 5 PubMed.

    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    View all comments by Nancy Ip

  2. We fully agree with Dr. Ip's insightful comments.

    View all comments by Anna Victoria Molofsky

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  1. Astrocytic IL-33 Signals Microglia to Engulf Synapses