Macrophage fusion induced by IL‐4 alternative activation is a multistage process involving multiple target molecules

Abstract

Multinucleated giant cells, characteristic of granulomatous infections, originate from fusion of macrophages, however, little is known about the underlying mechanism. Alternative activation of macrophages by exposure to IL-4 and IL-13 induces macrophage homokaryon formation. We have established a new quantitative bifluorescent system to study IL-4-induced fusion of primary murine macrophages in vitro. Using this assay, we could show that macrophage fusion is not mediated by a single molecule, but involves multiple functional components. Although several murine macrophage populations were not competent to form giant cells, indicating that they fail to display the full fusion machinery, these non-fusogenic macrophages could fuse with fusion-competent macrophages in a heterophilic manner. Since IL-4 induced molecules were needed on both fusion partners, we conclude that at least two functionally distinct molecules mediate macrophage homokaryon formation with each present on one fusion partner. In addition, though IL-4 treatment led to induction of a fusogenic status, macrophages could only fuse efficiently when adherent to a permissive substratum. Based on our findings, we conclude that macrophage fusion is a multistage process involving multiple target molecules. The model we describe will allow analysis of the molecular basis of membrane fusion and possible insight into alternative activation of macrophages. IntroductionFusion of cells is a fundamental biological process, yet very little is known about its mechanistic basis [1]. Cells of the monocyte/macrophage lineage can fuse and form large multinucleated giant cells (MGC) that have long been recognised as a histopathological hallmark of tuberculosis, schistosomiasis and other granulomatous diseases [2,3].To date, the function of MGC and their potential contribution to disease progression remain ill defined. However, macrophage fusion is also characteristic of osteoclast differentiation and foreign body granuloma formation, where fused macrophages ensure optimal degradation of bone and foreign material, respectively [2,4]. While intracellular and viral membrane fusion has been studied in detail, much less is known about the machinery that mediates cell-to-cell fusion, in particular macrophage homokaryon formation [1,5]. By analogy to virus-cell fusion, fusion of macrophages might be mediated by cell surface proteins [1]. Several individual candidate macrophage fusion molecules including dendritic cell-specific transmembrane protein (DC-STAMP), TREM2/DAP-12 (triggering receptor expressed on myeloid cells 2), MFR (macrophage fusion receptor), CD47, the mannose/fucose receptor and CD44 have been proposed, based on utilization of different experimental models [6][7][8][9][10][11][12][13]. However, there is no knowledge of their potential interplay and redundancy in the process of MGC formation. Alternative activation of macrophages by exposure to the type 2 cytokines IL-4 or IL-13 induces the formation of MGC in vitro [14][15][16]. Alternative activation of macrop...

Alternative activation of tumor-associated macrophages by IL-4

“…Helming and Gordon proposed a multistage model, in which IL-4 stimulation induces the expression of fusogenic molecules on macrophages, which mediate aggregation and membrane adhesion of adjacent macrophages, subsequently leading to cell fusion. 65,66 Several cell surface receptor proteins and adhesion molecules that are induced by IL-4 have been implicated in this process, including MMR, the scavenger receptor CD36, dendritic cell-specific transmembrane protein ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

New vistas on macrophage differentiation and activation

“…In the study by Helming and Gordon [6] in this issue of the Journal, the authors take advantage of a tagging strategy to determine that MGC formation is a multistep process associated with IL-4-driven alternative (M2) macrophage activation. The approach described in this study [6] is likely to pave the way to the identification of the pathways involved in and the function of MGC formation.In response to cytokines and microbial products, mononuclear phagocytes express specialized and polarized functional properties [1][2][3][4]. Mirroring the Th1/Th2 nomenclature, many refer to polarized macrophages as M1 and M2 cells.…”

“…Evidence published in this issue of the European Journal of Immunology, together with other recent data, add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation and are discussed in this Commentary. Heterogeneity and plasticity are hallmarks of cells belonging to the monocyte-macrophage lineage [1][2][3][4]. Lineage-defined populations of mononuclear phagocytes have not been identified, but already by the shortlived stage of circulating precursor monocytes subsets characterized by the differential expression of the FccRIII receptor (CD16) or of chemokine receptors (CCR2, CX3CR1 and CCR8) and by different functional properties have been described.…”

“…In response to cytokines and microbial products, mononuclear phagocytes express specialized and polarized functional properties [1][2][3][4]. Mirroring the Th1/Th2 nomenclature, many refer to polarized macrophages as M1 and M2 cells.…”

Гигантские Клетки Инородных Тел И Тканевые Реакции На Поверхности Имплантатов

“…Внутриклеточный домен CD44 (CD44ICD) отщепляется и транслоцируется в яд-ра клеток, где он способствует активации NF-kB. Коннексин 43 идентифицирован как фактор, иг-рающий роль в функционировании щелевидных межклеточных контактов в процессе формирова-ния ГКИТ при имплантации наночастиц гидрок-сиапатита [26]. Другим важным фактором адгезии и слияния макрофагов в ГКИТ является Е-кадгерин [24,36].…”