Nuclear Envelope Disruption Triggers Hallmarks of Aging in Lung Alveolar Macrophages

Silva, Nilushi De; Nader, Guilherme P.F.; Nadalin, Francesca; Azevedo, Kevin de; Couty, Mickaël; Bhargava, Anvita; Fouillade, Charles; Londoño-Vallejo, Arturo; Behrendt, Rayk; Gallwitz, Lisa; Säftig, Paul; Fernández, Beatriz Ruiz; Gonzales-Granado, Jose Maria; Niel, Guillaume van; Boissonnas, Alexandre; Piel, Matthieu; Manel, Nicolas

doi:10.2139/ssrn.4032934

Cited by 2 publications

(2 citation statements)

References 66 publications

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“…Regarding tissue-resident macrophages, lamin A/C ablation in immune cells results in a selective depletion of lung alveolar macrophages and a heightened susceptibility to influenza infection. 155 These alveolar macrophages also display DNA damage and p53-dependent senescence, hallmarks of inflammation and ageing, further confirming a potential role of nuclear lamina in macrophage function and inflammation. Finally, the overexpression of the lamin-A mutant progerin, a truncated version of the lamin-A protein, 156 which does not properly integrate into the lamina and disrupts the nuclear lamina meshwork, leads to significant disfigurement of the nucleus.…”

Section: Macrophage Polarization Induces Changes In Nuclear Morpholog...mentioning

confidence: 74%

Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?

2022

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Many inflammatory diseases that are responsible for a majority of deaths are still uncurable, in part as the underpinning pathomechanisms and how to combat them is still poorly understood. Tissue-resident macrophages play pivotal roles in the maintenance of tissue homeostasis, but if they gradually convert to proinflammatory phenotypes, or if blood-born proinflammatory macrophages persist long-term after activation, they contribute to chronic inflammation and fibrosis. While biochemical factors and how they regulate the inflammatory transcriptional response of macrophages have been at the forefront of research to identify targets for therapeutic interventions, evidence is increasing that physical factors also tune the macrophage phenotype. Recently, several mechanisms have emerged as to how physical factors impact the mechanobiology of macrophages, from the nuclear translocation of transcription factors to epigenetic modifications, perhaps even DNA methylation. Insight into the mechanobiology of macrophages and associated epigenetic modifications will deliver novel therapeutic options going forward, particularly in the context of increased inflammation with advancing age and age-related diseases. We review here how biophysical factors can co-regulate pro-inflammatory gene expression and epigenetic modifications and identify knowledge gaps that require urgent attention if this therapeutic potential is to be realized.

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Section: Macrophage Polarization Induces Changes In Nuclear Morpholog...mentioning

confidence: 74%

Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?

2022

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“…Our observation also highlights a tightly regulated balance between inward and outward budding of the endomembrane that involves lipid homeostasis and would regulate the coordination between concentration or retrieval of cargoes within the endosomal pathway. Further elucidation of the mechanisms discussed here may also help shed new light on pathogenetic mechanisms associated with CD63 74 or isoforms of ApoE with distinct affinity for cholesterol, with the interrelated functions of the retromer (VPS35) 75 and cholesterol in neurodegenerative diseases or with specific upregulation of CD63 in aging 77 and in cancer cells 78 . Finally , this new relation between CD63 and cholesterol could improve the use of CD63 as an engineered molecular tool to transform EVs into therapeutic shuttles 79 .…”

Section: Discussionmentioning

confidence: 96%

CD63 regulates cholesterol storage within endosomes and its distribution via exosomes

Palmulli

Couty

Piontek

et al. 2022

Preprint

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Exosomes are small extracellular vesicles that are enriched in specific proteins and lipids during their generation as intraluminal vesicles in multivesicular endosomes. Contrary to proteins, the endosomal sorting mechanisms of lipids on intraluminal vesicles are still ill-defined. Here, we find that the tetraspanin CD63, highly enriched in ILVs and exosomes, regulates cholesterol sorting on ILVs and exosomes. This process generates a pool of cholesterol that affects exosomes physical properties and can be mobilized by the NPC1/2 complex from ILVs and exosomes. Absence of CD63 redirects cholesterol from endosomes to the Trans-Golgi Network by actin dependent vesicular transport, placing CD63 and cholesterol at the center of a balance between inward and outward budding of endomembranes. These results establish CD63 as cholesterol sorting mechanism within endosomes and place ILVs and exosomes as alternative providers of cholesterol.

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Nuclear Envelope Disruption Triggers Hallmarks of Aging in Lung Alveolar Macrophages

Cited by 2 publications

References 66 publications

Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?

Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?

CD63 regulates cholesterol storage within endosomes and its distribution via exosomes

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