Lysosomal exocytosis by macrophages as a druggable mechanism for anti-inflammatory clearance of dead adipocytes in adipose tissue
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PROVIDER: PRJNA1314244 | ENA |
REPOSITORIES: ENA
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Project description:The clearance of dead adipocytes in adipose tissue (AT) poses a major challenge due to their large size, which exceeds the phagocytic capacity of macrophages and prevents classical, anti-inflammatory efferocytosis. Instead, adipose tissue macrophages (ATMs) accumulate around dying adipocytes, forming crown-like structures (CLS), and engage in lysosomal exocytosis – the extracellular degradation of adipocytes. In this study, we used an ex vivo explant model of murine epididymal white AT, cultured over seven days to investigate pharmacological strategies that modulate lysosomal exocytosis. We observed a progressive increase in CLS formation, secretion of the lysosomal enzymes ß-Hexosaminidase A (HEXA) and lysosomal acid lipase (LAL), and surface abundance of LAMP1 and LAMP2, confirming ATMs as key mediators of this process. Notably, activation of lysosomal exocytosis with the mTOR inhibitor Rapamycin enhanced adipocyte clearance and significantly reduced inflammatory ATM abundance and TNF-α secretion. Bulk RNA sequencing of ATMs revealed a highly significant impact of Rapamyin on ATM proliferation. In contrast, inhibition of lysosomal exocytosis with PIKfyve inhibitor Apilimod or targeted inhibition of LAL using Lalistat-2 disrupted lysosomal function and promoted a pro-inflammatory ATM phenotype. Our findings highlight lysosomal exocytosis as a critical pathway for the resolution of dead adipocytes and the regulation of inflammation in adipose tissue. Pharmacological enhancement of this process may represent a promising therapeutic approach to attenuate inflammation in AT and its metabolic consequences, including insulin resistance and type 2 diabetes.
2025-09-03 | GSE307090 | GEO
Project description:A protective role for APP in nuclear waste clearance via lysosomal exocytosis
| PRJNA1137394 | ENA
Project description:Amyloid precursor protein (APP) is widely known for its role in Alzheimer’s disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological function remains incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.
2026-06-11 | GSE272590 | GEO
Project description:Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Lipid reduction through cytoplasmic lipolysis might adversely worsen steatohepatitis, however, the effect of autophagic lipolysis, lipophagy, remains obscure. We engineered the adaptor protein to induce lipophagy with lipid droplet targeting signal and modified LC3 interacting region. Activating hepatocyte lipophagy obviously mitigated both steatosis and NASH pathology. Mechanistically, lipophagy promoted the excretion of lipid from liver via lysosomal exocytosis and attenuated harmful accumulation of nonesterified fatty acid. This exocytosis was dependent on Ca2+ signal unlike the lysosomal dysfunction-related exocytosis. High content compound screening identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin inhibited the transition to steatohepatitis in mice fed high fat with low methionine low choline diet. Given all these data, activating lipophagy may be a promising therapeutic approach to prevent NASH progression.
2023-05-15 | GSE185911 | GEO
Project description:Epigenetic changes drive differential gene expression, contributing to oncogenic transformation and drug resistance. Lysosomes are crucial in cell signaling and the sequestration of toxins and chemotherapeutic agents. This sequestration followed by expulsion through lysosomal exocytosis is a factor in drug resistance. The epigenetic regulation of lysosomal exocytosis remains poorly understood. Our research focuses on this regulation, hypothesizing that epigenetic modifier drugs (epidrugs) capable of inhibiting lysosomal exocytosis and could serve as potential therapeutics. Additionally, we investigate their potential synergy with drugs known to be sequestered in lysosomes. To examine this concept, we screened approximately 150 epigenetic drugs targeting various reader, writer, or eraser proteins. These drugs were assessed for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and on lysosomal biogenesis. Our findings reveal that among the epidrugs showing synergy with cisplatin and further reducing cell viability in combination, two type I PRMT inhibitors, MS023 and GSK3368715, inhibited lysosomal exocytosis. Notably, neither of these drugs altered the expression of the CLEAR lysosomal biogenesis network of genes, suggesting the involvement of novel regulators in lysosomal functions. To explore the specific components of the trafficking machinery affected by PRMT inhibitors, we conducted an RNA-seq analysis, uncovering several differentially expressed genes (DEGs). In addition to previously described functions such as methylation activity, or DNA repair; these DEGs included those involved in vesicular trafficking, lysosomal enzyme activity and lysosome dynamics, offering potential insights into the mechanism of reduced exocytosis and identifying a novel mode for its regulation. Additionally, both inhibitors exhibited synergy with other drugs known to be sequestered in lysosomes, such as carboplatin, oxaliplatin, sunitinib, and doxorubicin, indicating that inhibition of lysosomal exocytosis may be a common phenomenon for such drugs. These findings underscore the potential of Type I PRMT inhibitors as therapeutic agents in cancer treatment. Consistently, analysis on the publicly available patient data revealed that lower levels of type I PRMTs (PRMT1 and 6) were associated with better patient response to these drugs, further suggesting their potential as drug candidates for combination therapy to enhance chemotherapy efficacy and improve cancer patient survival rates.
2025-08-13 | GSE277490 | GEO
Project description: Not available
| S-EPMC12848297 | biostudies-literature
Project description:Lysosomes represent a heterogenous population of organelles whose optimal function is essential for early tissue development. The importance of this is evidenced by the number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. While it is clear that macromolecular accumulation can adversely impact tissue development, the full breadth of downstream pathways driving pathology in these disorders is yet to be elucidated. Recent studies support the existence of mechanisms beyond lysosomal storage that profoundly influence early tissue formation. Among these, impaired mitochondrial function, oxidative stress, inflammation, and abnormal growth factor signaling have been linked to early pathology in multiple LSD. Studies in zebrafish models of mucolipidosis II and sialidosis identified a mechanism whereby inappropriate secretion of lysosomal cathepsins disrupts the TGF-ß related signaling pathways that control skeletal formation. Here we demonstrate that loss of galns (N-acetyl galactosamine-6-sulfatase) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Along with changes in the activity of several cathepsin proteases, enhanced exocytosis disrupts TGFß and BMP signaling altering cartilage and bone development in galnsm/m mutant larvae. Together these data suggest a role for altered growth factor signaling in MPSIVA skeletal pathology.
2026-02-06 | GSE300957 | GEO
Project description:Liver lipophagy ameliorates nonalcoholic steatohepatitis through lysosomal lipid exocytosis
| PRJNA771352 | ENA
Project description:Amyloid precursor protein (APP) is widely known for its role in Alzheimer’s disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological function remains incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.
2026-06-11 | PXD053992 | Pride
Project description:Amyloid precursor protein (APP) is widely known for its role in Alzheimer’s disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological function remains incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.
2026-06-11 | PXD053993 | Pride