Lysosomal exocytosis by macrophages as a druggable mechanism for anti-inflammatory clearance of dead adipocytes in adipose tissue.
Level 5 - mechanism / opinion, no new human data
Ex vivo animal tissue bench research without human subjects
PubMed 41436477 · doi:10.1038/s41419-025-08334-0
What was done
Researchers evaluated the role of lysosomal exocytosis by adipose tissue macrophages (ATMs) in clearing dead adipocytes using an ex vivo explant model of murine epididymal white adipose tissue cultured over seven days. They tested pharmacological modulation using the mTOR inhibitor rapamycin to activate lysosomal exocytosis, as well as the PIKfyve inhibitor apilimod and the lysosomal acid lipase inhibitor Lalistat-2 to inhibit the pathway. Measurements included crown-like structure (CLS) formation, secretion of the lysosomal enzymes ß-Hexosaminidase A (HEXA) and lysosomal acid lipase (LAL), cell surface abundance of LAMP1 and LAMP2, TNF-α secretion, and bulk RNA sequencing of ATMs.
What was found
No quantitative figures, effect sizes, or p-values were reported in the abstract. Explants demonstrated progressive increases in CLS formation, secretion of HEXA and LAL, and surface levels of LAMP1 and LAMP2. Treatment with rapamycin enhanced dead adipocyte clearance, significantly reduced inflammatory ATM abundance, significantly decreased TNF-α secretion, and altered ATM proliferation pathways on bulk RNA sequencing. Conversely, inhibition of lysosomal exocytosis using apilimod or Lalistat-2 impaired lysosomal function and promoted a pro-inflammatory ATM phenotype.
Why it matters
This study delineates lysosomal exocytosis as a mechanistic pathway through which macrophages resolve hypertrophic dead adipocytes that cannot undergo standard efferocytosis. Pharmacologically promoting this clearance route may offer a strategy to alleviate chronic adipose tissue inflammation and associated metabolic dysregulation.
Limits
All findings derive from an ex vivo mouse explant model; there were no in vivo functional validations or human tissue experiments. The abstract omits sample sizes (n), quantitative data, and variance estimates. Systemic metabolic endpoints such as insulin resistance and glucose tolerance were not directly measured.
Cited by
- contradicts Crown-like structures observed in fat biopsies under microscopy represent dead macrophages surrounding adipocytes.