Macrophage Fusion and Multinucleated Giant Cells of Inflammation

Abstract

Macrophages undergo fusion with other macrophages to form the hallmark multinucleated giant cells of chronic inflammation. However, neither the existence of distinct morphological types of giant cells, the signaling pathways that induce their formation, the molecular mechanism(s) of macrophage fusion, nor the significance of macrophage multinucleation at chronic inflammatory sites are well understood. Our efforts have been focused on these unknowns, particularly as they relate to the foreign body-type giant cells that form on implanted biomaterials and biomedical devices. We have pursued the discoveries of human macrophage fusion factors (interleukin-4, interleukin-13, α-tocopherol) with emphasis on foreign body giant cells, and identified adhesion receptors and signaling intermediates, as well as an adhesion protein substrate (vitronectin) that supports macrophage fusion. Studies on the molecular mechanism of macrophage fusion have revealed it to be a mannose receptor-mediated phagocytic process with participation of the endoplasmic reticulum. Further phenotypic and functional investigations will foster new perspectives on these remarkable multinucleated cells and their physiological significances in multiple inflammatory processes.

Placental Macrophages Are Impaired in Chorioamnionitis, an Infectious Pathology of the Placenta

“…Because myeloid MGCs are characterized by specific concentrations of F-actin and the organization of their microtubules (17,30), we examined the cytoskeleton in placental MGCs. In pMw, F-actin was concentrated in dotted structures with a characteristic vinculin ring called podosomes (Fig.…”

“…Indeed, myeloid multinucleated giant cells (MGCs) are classified into several variants, including osteoclasts, Langhans cells, and foreign body-type giant cells (FBGs), each of which is characterized by distinct morphological and functional properties (16). Different stimuli have been reported to induce macrophage fusion (17); for example, monocytes treated with IFN-g and bacterial supernatants or lectins, such as Con A, differentiate in Langhans-like MGCs (18,19), whereas IL-4 or IL-13 stimulates the fusion of macrophages into FBG-like MGCs (17). The molecular mechanisms behind macrophage multinucleation are poorly understood, although molecules associated with chemotaxis, adhesion, and proteolysis have been shown to be required for inducing macrophage multinucleation (20).…”

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

“…This multifaceted response involves the participation of a number of inflammatory and fibrotic cell types including mast cells, neutrophils, monocytes/macrophages, lymphocytes, and fibroblasts. 7 In particular, long-term, chronic inflammation mediated by macrophages has been an active area of recent research (see McNally and Anderson for an excellent review 8 ). Activated macrophages adhere to implanted biomaterials and fuse to form multinucleated foreign body giant cells that persist at the implant site and promote granulation tissue formation, eventually leading to fibrous encapsulation.…”

“…Activated macrophages adhere to implanted biomaterials and fuse to form multinucleated foreign body giant cells that persist at the implant site and promote granulation tissue formation, eventually leading to fibrous encapsulation. 7,8 Complicating this is the issue of macrophage ''polarization.'' Macrophages can assume multiple phenotypes that can be broadly characterized as M1 ''classically activated'' or M2 ''alternatively activated'' phenotypes.…”

An <em>In Vitro</em> Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy

“…Interestingly, these cells are among the earliest characteristic changes in CNS tissue of GLD. This lack of knowledge may have been due to the assumption that the formation of multinucleated phagocytes, called giant cells in other diseases, are typically considered as a consequence of pathology rather than an initial pathogenic driving force 9 . Therefore, there have been few studies investigating the mechanism by which globoid cells are formed from phagocytes, particularly in the CNS of GLD.…”