Molecules regulating macrophage fusions

Multinuclear giant cells derived from hematopoietic stem cells or monocyte/macrophage lineage cells are subdivided into osteoclasts, bone resorbing cells, and macrophage giant cells (MGCs) including foreign body giant cells (hereafter described as FBGCs), which are induced at the site of implanted biomaterials, tumors, chronic inflammation and an infection such as tuberculosis. The most characteristic feature of these cells is multinucleation induced by the cell-cell fusion of mononuclear cells, a phenomenon first reported over 60 years ago. To date, combinations of cytokines for osteoclastogenesis or MGC formation have been identified, and osteoclasts and MGCs can be generated in the presence of specific combinations of cytokines in vitro. This makes it possible to isolate specific molecules for cell-cell fusion or to analyze the mechanisms and roles of multinucleation in osteoclasts and MGCs. Recent studies have accumulated data on molecules essential for the cell-cell fusion of osteoclasts and MGCs, and on the role of cell-cell fusion of osteoclasts and MGCs in bone homeostasis and foreign body reactions, respectively. Thus, the role of the cell-cell fusion of osteoclasts in bone homeostasis has been, at least in part, clarified. Furthermore, macrophages reportedly fuse not only with macrophages in a homophilic manner but also with somatic cells and tumors in a heterophilic manner, and the heterophilic fusion is considered involved in tissue repairs and tumor metastasis. Similar to this heterophilic cell-cell fusion, some types of virus such as human immune deficiency virus and influenza virus fuse to somatic cells during an infection. In this chapter, recent advances in the molecular understanding of cell-cell fusion in macrophages will be discussed.