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

The protective role of CD73 in periodontitis: preventing hyper-inflammatory fibroblasts and driving osteoclast energy metabolism

“…In other words, the CD73-dependent maximization of mitochondrial activity we observed in our model was followed by the optimization of osteoclast multinucleation, resulting in more bone resorption. Cell-cell fusion and multinucleation were previously described to enhance the mitochondrial activity required for resorptive activity in osteoclasts ( 38 ). Here we also show the lack of CD73 leads to intracellular H 2 O 2 accumulation, higher mitochondrial membrane potential and higher expression of the main subunits of the ETC, which have all been reported to be critical for the differentiation and survival of bone resorbing osteoclasts ( 27 , 39 ).…”