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McAlpine CS, Park J, Griciuc A, Kim E, Choi SH, Iwamoto Y, Kiss MG, Christie KA, Vinegoni C, Poller WC, Mindur JE, Chan CT, He S, Janssen H, Wong LP, Downey J, Singh S, Anzai A, Kahles F, Jorfi M, Feruglio PF, Sadreyev RI, Weissleder R, Kleinstiver BP, Nahrendorf M, Tanzi RE, Swirski FK. Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease. Nature. 2021 Jul;595(7869):701-706. Epub 2021 Jul 14 PubMed.
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NYU Langone
This presents an interesting take on AD research, and one that incorporates many non-neuronal, non-cell autonomous players—something that is always a more likely proposition for a disease as complex as AD.
The authors show that astrocyte-derived interleukin 3 (IL3) is able to induce expression/presentation of the IL3 receptor on microglia—integral for the enabling migration of microglia to amyloid plaques, and for the removal of pathogenic proteins in a mouse model of AD. Previous work has shown the IL3R is largely expressed in neural progenitor cells during development (Luo et al., 2012). The induction of both the IL3R and engagement of these migration and phagocytic pathways seems integral to staving off this particular part of the AD pathology puzzle.
More broadly, astrocyte-derived IL3 has been found to be: implicated as a microglial growth factor (Frei et al., 1986); important for neural development (Luo et al., 2012); protective to neurons in models of AD and Parkinson’s disease (Choudhury et al., 2011); likely playing a role in acute retinal injury (Lim et al., 2016). That this molecular signal is common across so many different diseases points to an important mechanism that is well-versed in responding to diverse insults and injuries.
One of the most intriguing aspects is how similar this response is to developmental IL3 signaling between astrocytes and microglia. Vainchtein and colleagues had previously shown that another interleukin—IL33—secreted by astrocytes is required for synapse engulfment during development (Vainchtein et al., 2018). Does IL3 have a similar developmental role? Do astrocytes, when faced with early brain pathology or a degenerating brain, re-engage these developmental mechanisms in an attempt to “rebuild” the brain’s architecture?
This is an intriguing possibility that many groups are now starting to investigate. How many of our “reactive” or “disease-responsive” cell phenotypes are actually “developmental” phenotypes, with brain-building mechanisms re-ignited to help rebuild sections of the brain damaged through disease and trauma? An intriguing hypothesis that work like this from McAlpine and colleagues is beginning to unravel.
References:
Choudhury ME, Sugimoto K, Kubo M, Nagai M, Nomoto M, Takahashi H, Yano H, Tanaka J. A cytokine mixture of GM-CSF and IL-3 that induces a neuroprotective phenotype of microglia leading to amelioration of (6-OHDA)-induced Parkinsonism of rats. Brain Behav. 2011 Sep;1(1):26-43. PubMed.
Frei K, Bodmer S, Schwerdel C, Fontana A. Astrocyte-derived interleukin 3 as a growth factor for microglia cells and peritoneal macrophages. J Immunol. 1986 Dec 1;137(11):3521-7. PubMed.
Lim JC, Lu W, Beckel JM, Mitchell CH. Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective. Front Cell Neurosci. 2016;10:270. Epub 2016 Nov 23 PubMed.
Luo XJ, Li M, Huang L, Nho K, Deng M, Chen Q, Weinberger DR, Vasquez AA, Rijpkema M, Mattay VS, Saykin AJ, Shen L, Fernández G, Franke B, Chen JC, Chen XN, Wang JK, Xiao X, Qi XB, Xiang K, Peng YM, Cao XY, Li Y, Shi XD, , Gan L, Su B. The interleukin 3 gene (IL3) contributes to human brain volume variation by regulating proliferation and survival of neural progenitors. PLoS One. 2012;7(11):e50375. PubMed.
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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