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Multinucleation resets human macrophages for specialized functions at the expense of their identity

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Title: Multinucleation resets human macrophages for specialized functions at the expense of their identity
Authors: Behmoaras, J
Item Type: Journal Article
Abstract: Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell–cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.
Issue Date: 6-Mar-2023
Date of Acceptance: 9-Dec-2022
URI: http://hdl.handle.net/10044/1/102210
DOI: 10.15252/embr.202256310
ISSN: 1469-221X
Publisher: Wiley
Start Page: 1
End Page: 19
Journal / Book Title: EMBO Reports
Volume: 24
Issue: 3
Copyright Statement: © 2023 The Authors. Published under the terms of the CC BY4.0 license.
Publication Status: Published
Online Publication Date: 2023-01-04
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine

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