Multinucleated Giant Cells: Current Insights in Phenotype, Biological Activities, and Mechanism of Formation

Abstract

Monocytes and macrophages are innate immune cells with diverse functions ranging from phagocytosis of microorganisms to forming a bridge with the adaptive immune system. A lesser-known attribute of macrophages is their ability to fuse with each other to form multinucleated giant cells. Based on their morphology and functional characteristics, there are in general three types of multinucleated giant cells including osteoclasts, foreign body giant cells and Langhans giant cells. Osteoclasts are bone resorbing cells and under physiological conditions they participate in bone remodeling. However, under pathological conditions such as rheumatoid arthritis and osteoporosis, osteoclasts are responsible for bone destruction and bone loss. Foreign body giant cells and Langhans giant cells appear only under pathological conditions. While foreign body giant cells are found in immune reactions against foreign material, including implants, Langhans giant cells are associated with granulomas in infectious and non-infectious diseases. The functionality and fusion mechanism of osteoclasts are being elucidated, however, our knowledge on the functions of foreign body giant cells and Langhans giant cells is limited. In this review, we describe and compare the phenotypic aspects, biological and functional activities of the three types of multinucleated giant cells. Furthermore, we provide an overview of the multinucleation process and highlight key molecules in the different phases of macrophage fusion.

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

“…RANKL, IFN-γ, IL-4). Following the differentiation step, cell fusion and multinucleation lead to mature LGCs, FBGCs and osteoclasts [1, 3]. Here we aimed to investigate the functional consequences of human macrophage fusion/multinucleation post-cell differentiation.…”

“…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 [1][2][3]. Osteoclasts are macrophage-derived multinucleated cells specialized in vertebrate bone remodelling and can be considered as homeostatic MGCs that turn-over during adult life [4].…”

“…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 [1]. FBGCs can be found at the site of implanted prostheses or medical devices [5] and are specialized in complement-mediated phagocytosis of large particles [6].…”

Neurodegeneration in a novel invertebrate model system: Failed microtubule‐mediated cell adhesion and unraveling of macroglia

“…Spider nephrocytes thus perform the function of brain‐derived macrophages comparable to those found in mammalian systems and are therefore important in the neuroimmune system (Lewcock et al., 2020). The upregulation of nephrocyte production in aging brain tissue is similar to inflammatory immune responses in mammals (Ahmadzadeh et al., 2022). Interestingly, multinucleated cells such as osteoclasts that contribute to the remodeling process of bone tissue were shown to cause breakdown of bone tissue under inflammatory conditions (Ahmadzadeh et al., 2022; Zuo & Deng, 2021).…”

“…The upregulation of nephrocyte production in aging brain tissue is similar to inflammatory immune responses in mammals (Ahmadzadeh et al., 2022). Interestingly, multinucleated cells such as osteoclasts that contribute to the remodeling process of bone tissue were shown to cause breakdown of bone tissue under inflammatory conditions (Ahmadzadeh et al., 2022; Zuo & Deng, 2021). It is thus expected that the nature of multinucleated complexes in spiders may similarly promote the breakdown of cell debris in old brain tissue.…”