Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

Cameron S. McAlpine, Joseph Park, Ana Griciuc, Eunhee Kim, Se Hoon Choi, Yoshiko Iwamoto, Máté G. Kiss, Kathleen A. Christie, Claudio Vinegoni, Wolfram C. Poller, John E. Mindur, Christopher T. Chan, Shun He, Henrike Janssen, Lai Ping Wong, Jeffrey Downey, Sumnima Singh, Atsushi Anzai, Florian Kahles, Mehdi Jorfi, Paolo Fumene Feruglio, Ruslan I. Sadreyev, Ralph Weissleder, Benjamin P. Kleinstiver, Matthias Nahrendorf, Rudolph E. Tanzi () and Filip K. Swirski ()
Additional contact information
Cameron S. McAlpine: Massachusetts General Hospital and Harvard Medical School
Joseph Park: Massachusetts General Hospital and Harvard Medical School
Ana Griciuc: Massachusetts General Hospital and Harvard Medical School
Eunhee Kim: Massachusetts General Hospital and Harvard Medical School
Se Hoon Choi: Massachusetts General Hospital and Harvard Medical School
Yoshiko Iwamoto: Massachusetts General Hospital and Harvard Medical School
Máté G. Kiss: Massachusetts General Hospital and Harvard Medical School
Kathleen A. Christie: Massachusetts General Hospital and Harvard Medical School
Claudio Vinegoni: Massachusetts General Hospital and Harvard Medical School
Wolfram C. Poller: Massachusetts General Hospital and Harvard Medical School
John E. Mindur: Massachusetts General Hospital and Harvard Medical School
Christopher T. Chan: Massachusetts General Hospital and Harvard Medical School
Shun He: Massachusetts General Hospital and Harvard Medical School
Henrike Janssen: Massachusetts General Hospital and Harvard Medical School
Lai Ping Wong: Massachusetts General Hospital
Jeffrey Downey: Massachusetts General Hospital and Harvard Medical School
Sumnima Singh: Massachusetts General Hospital and Harvard Medical School
Atsushi Anzai: Massachusetts General Hospital and Harvard Medical School
Florian Kahles: Massachusetts General Hospital and Harvard Medical School
Mehdi Jorfi: Massachusetts General Hospital and Harvard Medical School
Paolo Fumene Feruglio: University of Verona
Ruslan I. Sadreyev: Massachusetts General Hospital
Ralph Weissleder: Massachusetts General Hospital and Harvard Medical School
Benjamin P. Kleinstiver: Massachusetts General Hospital and Harvard Medical School
Matthias Nahrendorf: Massachusetts General Hospital and Harvard Medical School
Rudolph E. Tanzi: Massachusetts General Hospital and Harvard Medical School
Filip K. Swirski: Massachusetts General Hospital and Harvard Medical School

Nature, 2021, vol. 595, issue 7869, 701-706

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03734-6

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