They have also been proposed to play a role in viral persistence by acting as virus reservoirs since they are long-lived cells that are resistant to virus-induced cytotoxicity, cell host restriction, CD8+ T lymphocyte-mediated killing, and some antiretroviral therapies [68C73]. Heterotypic fusion Myeloid cells are able to fuse with poorly fusion competent cells. mediating the early stages of fusion, focusing on cell-surface receptors involved in the cell-to-cell adhesion steps that ultimately lead to multinucleation. Given that cell-to-cell fusion is a complex and well-coordinated process, we will also describe what is currently known about the evolution of F-actin-based structures involved in macrophage fusion, i.e., podosomes, zipper-like structures, and tunneling nanotubes (TNT). Finally, the localization and potential role of the key fusion mediators related to the formation of these F-actin structures will be discussed. This review intends to present the current status of knowledge of the molecular and cellular mechanisms supporting multinucleation of myeloid cells, highlighting the gaps still existing, and contributing to the proposition of potential disease-specific MGC markers and/or therapeutic targets. and HIV-1) leads to an increase in their ability to fuse and degrade the bone matrix [31C34]. However, the functionality of some proteins involved in OC fusion in vitro does not systematically correlate with altered OC differentiation or GSK3368715 dihydrochloride bone phenotype in vivo, at least under physiological conditions [35, 36]. These discrepancies Rabbit Polyclonal to CDK1/CDC2 (phospho-Thr14) between in vitro and in vivo observations will be discussed throughout this review. FBGCs commonly form at the tissue/material interface of implanted medical biomaterials or in tissues where foreign particles or organisms are too large to be phagocytosed [4, 7]. In response to these exogenous materials, acute and chronic inflammation occurs in a sequential fashion, leading to a local increase of interleukin-4 (IL-4) and interleukin-13 GSK3368715 dihydrochloride (IL-13). In vitro, IL-4- or IL-13- induced FBGC-like cells may have up to one hundred nuclei dispersed throughout the cytoplasm [37]. These MGCs exhibit specific cytokine secretion profiles and maintain some macrophage surface expression markers, whereas the CD14 monocyte marker is down-modulated, resulting in giant cells with a phenotype distinguishable from that of unfused macrophages and other MGCs [38C41]. This phenotype is dependent on material surface chemistry [42]. Although the exact role GSK3368715 dihydrochloride of FBGCs remains unclear, they are able to phagocytise large and complement-opsonized materials more efficiently than their unfused precursors, and their formation in vivo accompanies the elimination of complement-amyloid deposits [43, 44], suggesting that MGCs are more than the sum of their mononucleated macrophage counterparts. MGCs are also associated with pathological contexts such as lesions of Langerhans cell histiocytosis [45] and granuloma disorders including sarcoidosis [46], helminthic schistosomiasis [47], and microbial infections. The first granuloma was described by Langhans in the lungs in response to infection by (Mtb), the primary causative agent of tuberculosis [2]. In the early stages of infection, the granuloma consists of a compact and organized aggregate of epithelioid cells (highly specialized, differentiated macrophages) surrounded by a ring of lymphocytes. At later stages, the granuloma develops a fibrous capsid that isolates the core of infected macrophages, reduces vascularization, and thus limits bacilli spread. The plasticity of macrophages is essential for granuloma maturation and dynamics. In particular, macrophages can form MGCs or differentiate into foam cells, characterized by an accumulation of lipids [48]. It is generally accepted that these MGCs, called Langhans giant cells, result from cell-to-cell fusion under the control of inflammatory cytokines. However, it has been proposed that they can also result from defects in cell division [6, 49, 50]. In vitro, the combination of GM-CSF exposition with IFN- or IL-3 is sufficient to induce the formation of Langhans?giant-like cells with approximately 15 nuclei arranged in a circular pattern [37]. Moreover, within a human in vitro model of granuloma, the fusion of MGCs can be triggered by mycobacterial envelope glycolipids [51]. It remains unresolved whether these MGCs are beneficial or detrimental to the host, as granuloma aggregates restrain Mtb dissemination but do not eliminate all bacilli, promoting their persistence [52]. Several studies have made it possible to decipher their dual roles. In granuloma models, infection with a virulent strain of Mtb induces large MGCs that can no longer mediate bacterial uptake, whereas infection with less virulent species results in MGCs of smaller size but retaining phagocytic capabilities [53]. Moreover, following infection with Mtb, macrophages produce high levels of nitric oxide that drive the transformation of macrophages into giant cells permissive for bacilli persistence [54]. On the other hand, MGCs in tuberculous lymph-nodes highly express extracellular matrix-degrading enzymes, which may promote tissue damage [55]. It is clear that MGCs play a central role in the maintenance of chronic infection and associated tissue damage, however, their role during Mtb infection needs to be further clarified. Virus-induced fusion of macrophages and more generally of myeloid cells, to our knowledge, has only been studied in the context of HIV-1 infection. Membrane fusion is a mechanism commonly used by several families of enveloped viruses (e.g., Herpesviridae, Paramyxoviridae, Flaviridae, Retroviridae or Coronaviridae) to enter target cells. This process is mediated by fusogenic proteins of the.
They have also been proposed to play a role in viral persistence by acting as virus reservoirs since they are long-lived cells that are resistant to virus-induced cytotoxicity, cell host restriction, CD8+ T lymphocyte-mediated killing, and some antiretroviral therapies [68C73]
