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1.
Results Probl Cell Differ ; 73: 419-434, 2024.
Article de Anglais | MEDLINE | ID: mdl-39242388

RÉSUMÉ

Tunneling nanotubes (TNTs) are cellular connections, which represent a novel route for cell-to-cell communication. Strong evidence points to a role for TNTs in the intercellular transfer of signals, molecules, organelles, and pathogens, involving them in many cellular functions. In myeloid cells (e.g., monocytes/macrophages, dendritic cells, and osteoclasts), intercellular communication via TNT contributes to their differentiation and immune functions, by favoring material and pathogen transfer, as well as cell fusion. This chapter addresses the complexity of the definition and characterization of TNTs in myeloid cells, the different processes involved in their formation, their existence in vivo, and finally their function(s) in health and infectious diseases, with the example of HIV-1 infection.


Sujet(s)
Communication cellulaire , Cellules myéloïdes , Humains , Communication cellulaire/physiologie , Animaux , Infections à VIH/immunologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/physiologie , Structures de la membrane cellulaire , Nanotubes
2.
Elife ; 132024 Jun 05.
Article de Anglais | MEDLINE | ID: mdl-38836552

RÉSUMÉ

Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human NINEIN gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts, whereas the number of osteoblasts remains unaffected. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.


Sujet(s)
Souris knockout , Protéines nucléaires , Ostéoclastes , Ostéogenèse , Animaux , Souris , Centrosome/métabolisme , Protéines nucléaires/métabolisme , Protéines nucléaires/génétique , Ostéoblastes/métabolisme , Ostéoclastes/métabolisme
3.
bioRxiv ; 2024 Aug 28.
Article de Anglais | MEDLINE | ID: mdl-38798563

RÉSUMÉ

Cell-cell fusion is an evolutionarily conserved process that is essential for many functions, including fertilisation and the formation of placenta, muscle and osteoclasts, multinucleated cells that are unique in their ability to resorb bone. The mechanisms of osteoclast multinucleation involve dynamic interactions between the actin cytoskeleton and the plasma membrane that are still poorly characterized. Here, we found that moesin, a cytoskeletal linker protein member of the Ezrin/Radixin/Moesin (ERM) protein family, is activated during osteoclast maturation and plays an instrumental role in both osteoclast fusion and function. In mouse and human osteoclast precursors, moesin inhibition favors their ability to fuse into multinucleated osteoclasts. Accordingly, we demonstrated that moesin depletion decreases membrane-to-cortex attachment and enhances the formation of tunneling nanotubes (TNTs), F-actin-based intercellular bridges that we reveal here to trigger cell-cell fusion. Moesin also controls HIV-1- and inflammation-induced cell fusion. In addition, moesin regulates the formation of the sealing zone, the adhesive structure determining osteoclast bone resorption area, and thus controls bone degradation, via a ß3-integrin/RhoA/SLK pathway. Supporting our results, moesin - deficient mice present a reduced density of trabecular bones and increased osteoclast abundance and activity. These findings provide a better understanding of the regulation of cell-cell fusion and osteoclast biology, opening new opportunities to specifically target osteoclast activity in bone disease therapy.

4.
Elife ; 112022 06 21.
Article de Anglais | MEDLINE | ID: mdl-35727134

RÉSUMÉ

Osteoclasts are unique in their capacity to degrade bone tissue. To achieve this process, osteoclasts form a specific structure called the sealing zone, which creates a close contact with bone and confines the release of protons and hydrolases for bone degradation. The sealing zone is composed of actin structures called podosomes nested in a dense actin network. The organization of these actin structures inside the sealing zone at the nano scale is still unknown. Here, we combine cutting-edge microscopy methods to reveal the nanoscale architecture and dynamics of the sealing zone formed by human osteoclasts on bone surface. Random illumination microscopy allowed the identification and live imaging of densely packed actin cores within the sealing zone. A cross-correlation analysis of the fluctuations of actin content at these cores indicates that they are locally synchronized. Further examination shows that the sealing zone is composed of groups of synchronized cores linked by α-actinin1 positive filaments, and encircled by adhesion complexes. Thus, we propose that the confinement of bone degradation mediators is achieved through the coordination of islets of actin cores and not by the global coordination of all podosomal subunits forming the sealing zone.


Sujet(s)
Résorption osseuse , Podosomes , Cytosquelette d'actine/métabolisme , Actines/métabolisme , Résorption osseuse/métabolisme , Cytosquelette/métabolisme , Humains , Ostéoclastes/métabolisme , Podosomes/métabolisme
5.
Cell Mol Life Sci ; 78(17-18): 6087-6104, 2021 Sep.
Article de Anglais | MEDLINE | ID: mdl-34296319

RÉSUMÉ

Different types of multinucleated giant cells (MGCs) of myeloid origin have been described; osteoclasts are the most extensively studied because of their importance in bone homeostasis. MGCs are formed by cell-to-cell fusion, and most types have been observed in pathological conditions, especially in infectious and non-infectious chronic inflammatory contexts. The precise role of the different MGCs and the mechanisms that govern their formation remain poorly understood, likely due to their heterogeneity. First, we will introduce the main populations of MGCs derived from the monocyte/macrophage lineage. We will then discuss the known molecular actors 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.


Sujet(s)
Adhérence cellulaire , Cellules géantes/métabolisme , Cellules myéloïdes/métabolisme , Podosomes/métabolisme , Cellules géantes/cytologie , Humains , Intégrines/métabolisme , Macrophages/cytologie , Macrophages/métabolisme , Cellules myéloïdes/cytologie , Cellules myéloïdes/ultrastructure , Ostéoclastes/cytologie , Ostéoclastes/métabolisme , Ostéogenèse , Récepteurs immunologiques/métabolisme
6.
J Pharmacol Exp Ther ; 369(1): 144-151, 2019 04.
Article de Anglais | MEDLINE | ID: mdl-30670479

RÉSUMÉ

Adenosine receptors (ARs) represent key drug targets in many human pathologies, including cardiovascular, neurologic, and inflammatory diseases. To overcome the very rapid metabolization of adenosine, metabolically stable AR agonists and antagonists were developed. However, few of these molecules have reached the market due to efficacy and safety issues. Conjugation of adenosine to squalene to form squalene-adenosine (SQAd) nanoparticles (NPs) dramatically improved the pharmacological efficacy of adenosine, especially for neuroprotection in stroke and spinal cord injury. However, the mechanism by which SQAd NPs displayed therapeutic activity remained totally unknown. In the present study, two hypotheses were discussed: 1) SQAd bioconjugates, which constitute the NP building blocks, act directly as AR ligands; or 2) adenosine, once released from intracellularly processed SQAd NPs, interacts with these receptors. The first hypothesis was rejected, using radioligand displacement assays, as no binding to human ARs was detected, up to 100 µM SQAd, in the presence of plasma. Hence, the second hypothesis was examined. SQAd NPs uptake by HepG2 cells, which was followed using radioactive and fluorescence tagging, was found to be independent of equilibrative nucleoside transporters but rather mediated by low-density lipoprotein receptors. Interestingly, it was observed that after cell internalization, SQAd NPs operated as an intracellular reservoir of adenosine, followed by a sustained release of the nucleoside in the extracellular medium. This resulted in a final paracrine-like activation of the AR pathway, evidenced by fluctuations of the second messenger cAMP. This deeper understanding of the SQAd NPs mechanism of action provides a strong rational for extending the pharmaceutical use of this nanoformulation.


Sujet(s)
Adénosine/composition chimique , Adénosine/métabolisme , Nanoparticules/composition chimique , Promédicaments/métabolisme , Récepteurs purinergiques P1/métabolisme , Squalène/composition chimique , Squalène/métabolisme , Animaux , Transport biologique , Cellules CHO , Cricetulus , Espace extracellulaire/métabolisme , Cellules HEK293 , Cellules HepG2 , Humains , Concentration en ions d'hydrogène , Ligands
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