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McAlpine, Cameron

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McAlpine

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Cameron

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McAlpine, Cameron

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2016 - 201922020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.524000ff-c10e-401d-be0b-f847c40b7eb8

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    Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
    (Springer Science and Business Media LLC, 2021-07-14) McAlpine, Cameron; Park, Joseph; Griciuc, Ana; Kim, Eunhee; Choi, Se Hoon; Iwamoto, Yoshiko; Kiss, Máté G.; Christie, Kathleen; Vinegoni, Claudio; Poller, Wolfram; Mindur, John; Chan, Christopher; He, Shun; Janssen, Henrike; Wong, Lai Ping; Downey, Jeffrey; Singh, Sumnima; Anzai, Atsushi; Kahles, Florian; Jorfi, Mehdi; Feruglio, Paulo; Sadreyev, Ruslan; Weissleder, Ralph; Kleinstiver, Benjamin; Nahrendorf, Matthias; Tanzi, Rudolph; Swirski, Filip
    Communication within the glial cell ecosystem is essential to neuronal and brain health1–3. The influence of glial cells on β-amyloid (Aβ) and neurofibrillary tau accumulation and clearance in 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) reprograms microglia to ameliorate AD pathology. Upon recognition of Aβ deposits, microglia augment IL-3Rɑ, IL-3’s specific receptor, rendering them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional reprograming of microglia endowing them with an acute immune response program, enhanced motility, and the capacity to cluster and clear Aβ and tau aggregates. These changes restrict AD pathology and cognitive decline. This study identifies IL-3 as a critical mediator of astrocyte-microglia crosstalk and a node for therapeutic intervention in AD.
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    The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes
    (The Rockefeller University Press, 2017) Anzai, Atsushi; Choi, Jennifer; He, Shun; Fenn, Ashley M.; Nairz, Manfred; Rattik, Sara; McAlpine, Cameron; Mindur, John; Chan, Christopher; Iwamoto, Yoshiko; Tricot, Benoit; Wojtkiewicz, Gregory R.; Weissleder, Ralph; Libby, Peter; Nahrendorf, Matthias; Stone, James; Becher, Burkhard; Swirski, Filip
    Myocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells. In the heart, fibroblast-derived GM-CSF alerts its neighboring myeloid cells to attract neutrophils and monocytes. The growth factor also reaches the bone marrow, where it stimulates a distinct myeloid-biased progenitor subset. Consequently, hearts of mice deficient in either GM-CSF or its receptor recruit fewer leukocytes and function relatively well, whereas mice producing GM-CSF can succumb from left ventricular rupture, a complication mitigated by anti–GM-CSF therapy. These results identify GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target, bolstering the idea that GM-CSF is a major orchestrator of the leukocyte supply chain during inflammation.
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    On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver
    (2016) Theurl, Igor; Hilgendorf, Ingo; Nairz, Manfred; Tymoszuk, Piotr; Haschka, David; Asshoff, Malte; He, Shun; Gerhardt, Louisa M. S.; Holderried, Tobias A. W.; Seifert, Markus; Sopper, Sieghart; Fenn, Ashley; Anzai, Atsushi; Rattik, Sara; McAlpine, Cameron; Theurl, Milan; Wieghofer, Peter; Iwamoto, Yoshiko; Weber, Georg F.; Harder, Nina K.; Chousterman, Benjamin G.; Arvedson, Tara L.; McKee, Mary; Wang, Fudi; Lutz, Oliver M. D.; Rezoagli, Emanuele; Babitt, Jodie; Berra, Lorenzo; Prinz, Marco; Nahrendorf, Matthias; Weiss, Guenter; Weissleder, Ralph; Lin, Herbert; Swirski, Filip
    Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.