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Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density

Howard S Kruth1, Nancy L Jones, Wei Huang

  • 1Section of Experimental Atherosclerosis, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1422, USA. kruthh@nhlbi.nih.gov

The Journal of Biological Chemistry
|November 10, 2004
PubMed

Insights

Macropinocytosis, a fluid-phase endocytosis pathway, drives LDL uptake in macrophages, leading to cholesterol accumulation and foam cell formation. This novel pathway offers a new target for atherosclerosis treatment.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Macrophages play a key role in atherosclerosis by accumulating cholesterol.
  • Fluid-phase endocytosis is a cellular uptake mechanism for fluids and particles.
  • Low-density lipoprotein (LDL) uptake by macrophages contributes to foam cell formation.

Purpose of the Study:

  • To identify the specific endocytic pathway responsible for fluid-phase LDL uptake in macrophages.
  • To elucidate the signaling and cytoskeletal mechanisms involved in this LDL endocytosis.
  • To investigate the fate of internalized LDL and its contribution to foam cell formation.

Main Methods:

  • Utilized phosphatidylinositol 3-kinase inhibitor LY294002 to differentiate between macropinocytosis and micropinocytosis.
  • Employed nystatin and filipin to assess the role of lipid-raft dependent endocytosis.
  • Applied time-lapse microscopy (phase-contrast and confocal fluorescence) with fluorescently labeled LDL (DiI-LDL).
  • Investigated the effect of vacuolar H+-ATPase inhibitor bafilomycin A1 on LDL degradation.

Main Results:

  • Macropinocytosis, not micropinocytosis, was identified as the primary pathway for fluid-phase LDL uptake in PMA-activated macrophages.
  • Inhibition of macropinocytosis by LY294002 completely blocked LDL uptake, while micropinocytosis inhibitors had no effect.
  • Rho GTPase signaling, actin, and microtubules were essential for macropinocytosis of LDL.
  • Bafilomycin A1 treatment inhibited LDL degradation and led to LDL accumulation within macropinosomes and multivesicular bodies, indicating macropinosome maturation and shrinkage.
  • LDL concentration increased significantly within multivesicular body endosomes.

Conclusions:

  • Macropinocytosis of LDL, independent of receptor-mediated binding, is a novel pathway for generating macrophage foam cells.
  • This macropinocytosis pathway represents a new therapeutic target for modulating foam cell formation in atherosclerosis.
  • The findings highlight the importance of macropinocytosis in cellular lipid metabolism and cardiovascular disease progression.

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