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An actin-based protrusion originating from a podosome-enriched region initiates macrophage fusion

James J. Faust, Arnat Balabiyev, John M. Heddleston, Nataly P. Podolnikova, Debra Page Baluch, Teng-Leong Chew, Tatiana Ugarova
doi: https://doi.org/10.1101/538314
James J. Faust
Department of Cell and Developmental Biology, Vanderbilt University, School of Medicine;
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  • For correspondence: james.j.faust@vanderbilt.edu
Arnat Balabiyev
School of Life Sciences, Arizona State University;
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  • For correspondence: abalabiy@asu.edu
John M. Heddleston
Advanced Imaging Center, HHMI Janelia Research Campus
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  • For correspondence: heddlestonj@janelia.hhmi.org
Nataly P. Podolnikova
School of Life Sciences, Arizona State University;
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  • For correspondence: nataly.podolnikova@asu.edu
Debra Page Baluch
School of Life Sciences, Arizona State University;
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  • For correspondence: page.baluch@asu.edu
Teng-Leong Chew
Advanced Imaging Center, HHMI Janelia Research Campus
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  • For correspondence: chewt@janelia.hhmi.org
Tatiana Ugarova
School of Life Sciences, Arizona State University;
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  • For correspondence: tatiana.ugarova@asu.edu
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Abstract

Macrophage fusion resulting in the formation of multinucleated giant cells occurs in a variety of chronic inflammatory diseases, yet the mechanism responsible for initiating macrophage fusion is unknown. Here, we used live cell imaging to show that actin-based protrusions at the leading edge initiate macrophage fusion. Phase contrast video microscopy demonstrated that in the majority of events, short protrusions (3 ± 1 μm) between two closely apposed cells initiated fusion, but occasionally we observed long protrusions (16 ± 7 μm). Using macrophages isolated from LifeAct mice and imaging with lattice light sheet microscopy, we further found that fusion-competent actin-based protrusions formed at sites enriched in podosomes. Inducing fusion in mixed populations of GFP- and mRFP-LifeAct macrophages showed rapid spatial overlap between GFP and RFP signal at the site of fusion. Cytochalasin B strongly reduced fusion and when rare fusion events occurred, protrusions were not observed. Fusion of macrophages deficient in Wiskott-Aldrich syndrome protein and Cdc42, key molecules involved in the formation of actin-based protrusions and podosomes, was also impaired both in vitro and in vivo. Finally, inhibiting the activity of the Arp2/3 complex decreased fusion and podosome formation. Together these data indicate that an actin-based protrusion formed at the leading edge macrophage fusion.

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Posted February 04, 2019.
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An actin-based protrusion originating from a podosome-enriched region initiates macrophage fusion
James J. Faust, Arnat Balabiyev, John M. Heddleston, Nataly P. Podolnikova, Debra Page Baluch, Teng-Leong Chew, Tatiana Ugarova
bioRxiv 538314; doi: https://doi.org/10.1101/538314
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An actin-based protrusion originating from a podosome-enriched region initiates macrophage fusion
James J. Faust, Arnat Balabiyev, John M. Heddleston, Nataly P. Podolnikova, Debra Page Baluch, Teng-Leong Chew, Tatiana Ugarova
bioRxiv 538314; doi: https://doi.org/10.1101/538314

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