Lysosomal Dysfunction-Mediated IgG Accumulation Promotes Endothelial Senescence and Lesion Progression in Cerebral Cavernous Malformations
Yang, Y.; sun, y.; Zhao, S.; Zhou, Q.; Wang, H.; Sun, R.; Huo, R.; Dao, L.; Xu, Z.; Liu, J.; Zhai, R. G.; Chen, y.; Zhang, Q.; Guo, Z.; Ho, W. S.; Wang, J.; Lu, R. O.; Cao, Y.
Show abstract
Endothelial senescence is increasingly recognized as a driver of vascular pathology, while immunoglobulin G (IgG) has recently been reported to accumulate in aging tissues and induce senescence in macrophages and microglia. In cerebral cavernous malformations (CCMs), IgG accumulation has been obviously observed in CCM lesions, but the contribution of IgG to endothelial injury remains unclear. Using multi-omic profiling, endothelial models, and CCM mice, we identified IgG-secreting plasma cells enriched in lesions associated with endothelial senescence, hemorrhage, and disease severity. CCM loss-associated mTOR activation impaired lysosomal acidification and IgG processing, promoting intracellular IgG accumulation. IgG, in turn, induced NF-kB-dependent endothelial senescence. In vivo, BCMA-mediated plasma cell depletion attenuated lesion progression, whereas IgG supplementation partially restored disease severity. Anti-CD38 treatment likewise reduced IgG accumulation, endothelial senescence, hemorrhage, and lesion progression. These findings identify lysosomal dysfunction-mediated IgG as a pathogenic trigger of endothelial senescence and support targeting the plasma cell-IgG axis in CCM.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Single-Cell Analysis Reveals Critical Role of Macrophage Epsin in Regulating Origin of Foam Cell in Atherosclerosis 93%
- High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis 93%
- Single-Cell Multimodal Profiling Reveals a Novel CD26+ Fibroblast Subpopulation in Atherosclerosis 92%
Similar papers in this journal
Similar papers in this journal
- Oxidative DNA Damage Drives Apoptotic Photoreceptor Loss in NMNAT1-Associated Inherited Retinal Degeneration: A Therapeutic Opportunity 90%
- Neutrophil Reprogramming Underlie Vasculopathy and Lung Disease in Systemic Sclerosis 89%
- Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling 88%
Similar papers in this journal
- Apolipoprotein E isoform-specific phase transitions in the retinal pigment epithelium drive disease phenotypes in age-related macular degeneration 92%
- PI3Kγ promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm 90%
- Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice 90%
Similar papers in this journal
- Rare coding variants in CTSO, a potential new actor of arterial remodeling, are associated to familial intracranial aneurysm 95%
- Delineation of a thrombin receptor-stimulated vascular smooth muscle cell transition generating cells in the plaque-stabilising fibrous cap 93%
- Crosstalk of platelets with macrophages and fibroblasts aggravates inflammation, aortic wall stiffening, and osteopontin release in abdominal aortic aneurysm 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.