TY - JOUR
T1 - Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
AU - McAlpine, Cameron S.
AU - Park, Joseph
AU - Griciuc, Ana
AU - Kim, Eunhee
AU - Choi, Se Hoon
AU - Iwamoto, Yoshiko
AU - Kiss, Máté G.
AU - Christie, Kathleen A.
AU - Vinegoni, Claudio
AU - Poller, Wolfram C.
AU - Mindur, John E.
AU - Chan, Christopher T.
AU - He, Shun
AU - Janssen, Henrike
AU - Wong, Lai Ping
AU - Downey, Jeffrey
AU - Singh, Sumnima
AU - Anzai, Atsushi
AU - Kahles, Florian
AU - Jorfi, Mehdi
AU - Feruglio, Paolo Fumene
AU - Sadreyev, Ruslan I.
AU - Weissleder, Ralph
AU - Kleinstiver, Benjamin P.
AU - Nahrendorf, Matthias
AU - Tanzi, Rudolph E.
AU - Swirski, Filip K.
N1 - Funding Information:
Acknowledgements We thank the HCI-CRM Flow Cytometry Core Facility at the Massachusetts General Hospital for assistance in cell sorting; the MGH DF/HCC Specialized Histopathology Services core and the Hope Babette Tang Histology Facility at the Massachusetts Institute of Technology for tissue sectioning and histology services; the MGH NexGen sequencing and Bioinformatics facility for RNA-seq experiments and analysis; L. Wu and the Harvard Genome Modification Facility for help generating mice; G. Wojtkiewicz for help with imaging software; and K. Joyes for copy editing. This work was funded by the Cure Alzheimer’s Fund, the National Institutes of Health (NIH) R35 HL135752, P01 HL131478, P01 HL142494, and the Patricia and Scott Eston MGH Research Scholar (to F.K.S.); NIH K99/R00 HL151750, R01 HL158534, and a Canadian Institutes of Health Research Banting Fellowship (to C.S.M.); HL142494 (to M.N. and B.P.K); NIH R35HL139598 (to M.N.); NIH Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship F31HL147364 (to J.E.M.); and NIH R00 CA218870 (to B.P.K.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/29
Y1 - 2021/7/29
N2 - Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD.
AB - Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD.
UR - http://www.scopus.com/inward/record.url?scp=85111653296&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03734-6
DO - 10.1038/s41586-021-03734-6
M3 - Article
C2 - 34262178
AN - SCOPUS:85111653296
VL - 595
SP - 701
EP - 706
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7869
ER -