Biology subjects

Mascarau, R.

Publications and source records attributed to Mascarau, R..

3 recordsLinked to original sources

bioRxiv2024

Moesin activation controls bone resorption and tunneling nanotube-dependent osteoclast fusion

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 {beta}3-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.

cell biology↗

bioRxiv2020

HIV-1-infected human macrophages, by secreting RANKL, contribute to enhanced osteoclastogenesis

HIV-1 infection is frequently associated with low bone density, which can progress to osteoporosis leading to a high risk of fractures. Only a few mechanisms have been proposed to explain the enhanced osteolysis in the context of HIV-1 infection. As macrophages are involved in bone homeostasis and are critical cell hosts for HIV-1, we asked whether HIV-1-infected macrophages could participate in bone degradation. Upon infection, human macrophages acquired some osteoclast features: they became multinucleated, upregulated the osteoclast markers RhoE and {beta}3 integrin, and organized their podosomes as ring superstructures resembling osteoclast sealing zones. However, HIV-1 infected macrophages were not fully differentiated in osteoclasts as they did not upregulate NFATc-1 transcription factor and were unable to degrade bone. Investigating whether infected macrophages participate indirectly to virus-induced osteolysis, we showed that they produce RANKL, the key osteoclastogenic cytokine. RANK-L secreted by HIV-1-infected macrophages was not sufficient to stimulate multinucleation, but promoted the protease-dependent migration of osteoclast precursors. In conclusion, we propose that, by stimulating RANKL secretion, HIV-1-infected macrophages contribute to create a microenvironment that favors the recruitment of osteoclasts, participating to bone disorders observed in HIV-1+ patients.

cell biology↗

bioRxiv2019

Mycobacterium tuberculosis Modulates the Metabolism of Alternatively Activated Macrophages to Promote Foam Cell Formation and Intracellular Survival

The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM). Indeed, FM are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate if distinct macrophage activation states exposed to a tuberculosis-associated microenvironment can accumulate LBs, and its impact on the control of infection. We showed that signal transducer and activator of transcription 6 (STAT6) activation in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the {beta}-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. We demonstrated that inhibition of the lipolytic activity or of the FAO drives M(IL-4) macrophages into FM. Also, exhibiting a predominant FAO metabolism, mouse alveolar macrophages are less prone to become FM compared to bone marrow derived-macrophages. Upon Mtb infection, M(IL-4) macrophages are metabolically re-programmed towards the aerobic glycolytic pathway and evolve towards a foamy phenotype, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1)-induced glycolytic pathway. In conclusion, our results demonstrate a role for STAT6-driven FAO in preventing FM differentiation, and reveal an extraordinary capacity by Mtb to rewire metabolic pathways in human macrophages and induce the favorable FM. IMPORTANCETuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). While its treatment was already standardized, TB remains one of the top 10 death causes worldwide. A major problem is the efficient adaptation of Mtb to the macrophage intracellular milieu, which includes deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM) which are favorable to Mtb. A critical aspect of our work is the use of tuberculous pleural effusions (TB-PE) -- human-derived biological fluid capable of mimicking the complex microenvironment of the lung cavity upon Mtb infection -- to study the FM metabolic modulation. We revealed how the STAT6 transcription factor prevents FM formation induced by PE-TB, and how Mtb counteracts it by activating another transcription factor, HIF-1, to re-establish FM. This study provides key insights in host lipid metabolism, macrophage biology and pathogen subversion strategies, to be exploited for prevention and therapeutic purposes in infectious diseases.

immunology↗