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

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. While osteoclast multinucleation is a prerequisite for vertebrate bone homeostasis, the effector function resulting from LGC and FBGC multinucleation is less well-defined. More generally, how multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrated 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 down-regulation of mononuclear phagocyte 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, only B7-H3 (CD276)-expressing human LGCs can form granuloma-like clusters in vitro, suggesting that LGC 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.

Osteoimmune regulation underlies oral implant osseointegration and its perturbation

“…It is important to note that M1-MNGCs may express a different repertoire or concentration of inflammatory factors (cytokines and chemokines), which are also time-dependent if M1-MNGCs switch towards an antiinflammatory phenotype. Therefore, the FBR could differ between different biomaterials (71). In fact, the results of FBR, such as chronic inflammation, excessive granulation, collagen fiber deposition, and fibrous tissue formation, are related to the persistence of a microenvironment with upregulation of genes related to inflammation (IL-1) and the ability of the biomaterial to continue serving as an immunomodulator (72).…”

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

“…RANKL, IFN-c, IL-4). Following the differentiation step, cell fusion and multinucleation lead to mature LGCs, FBGCs and osteoclasts (Pereira et al, 2018;Ahmadzadeh et al, 2022). Here, we aimed to investigate the functional consequences of human macrophage fusion/multinucleation post-cell differentiation.…”

“…Conversely, LGCs and FBGCs are preferentially found in pathological sites during inflammatory processes. LGCs are the hallmark of infectious (tuberculosis) and non-infectious (sarcoidosis, Blau syndrome) granulomatous diseases (Ahmadzadeh et al, 2022). FBGCs can be found at the site of implanted prostheses or medical devices (Anderson et al, 2008) and are specialized in complement-mediated phagocytosis of large particles (Milde et al, 2015).…”

“…Cell-cell fusion in monocyte/macrophage lineage leads to the formation of diverse multinucleated giant cells (MGCs), depending on the tissue microenvironment. MGCs can be classified into osteoclasts, Langhans giant cells (LGCs) and foreign body giant cells (FBGCs), on the basis of their anatomical site, morphology and function during homeostasis or inflammatory disease (Helming & Gordon, 2007;Pereira et al, 2018;Ahmadzadeh et al, 2022). Osteoclasts are macrophage-derived multinucleated cells specialized in vertebrate bone remodeling and can be considered as homeostatic MGCs that turn-over during adult life (Boyle et al, 2003).…”

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

“…Cell-cell fusion in monocyte/macrophage lineage leads to the formation of diverse multinucleated giant cells (MGCs), depending on the tissue microenvironment. MGCs can be classified into osteoclasts, Langhans giant cells (LGCs) and foreign body giant cells (FBGCs), on the basis of their anatomical site, morphology and function during homeostasis or inflammatory disease (Helming & Gordon, 2007;Pereira et al, 2018;Ahmadzadeh et al, 2022). Osteoclasts are macrophage-derived multinucleated cells specialized in vertebrate bone remodeling and can be considered as homeostatic MGCs that turn-over during adult life (Boyle et al, 2003).…”