title: Degradation and beyond: the macrophage lysosome as a nexus for nutrient sensing and processing in atherosclerosis.
abstract: OBJECTIVE
  The ability of macrophage lysosomes to degrade both exogenous and internally derived cargo is paramount to handling the overabundance of lipid and cytotoxic material present in the atherosclerotic plaque. We will discuss recent insights in both classical and novel functions of the lysosomal apparatus, as it pertains to the pathophysiology of atherosclerosis.
  
  
  RESULTS
  Lipid-mediated dysfunction in macrophage lysosomes appears to be a critical event in plaque progression. Consequences include enhanced inflammatory signalling [particularly the inflammasome/interleukin-1β axis] and an inability to interface with autophagy leading to a proatherogenic accumulation of dysfunctional organelles and protein aggregates. Aside from degradation, several novel functions have recently been ascribed to lysosomes, including involvement in macrophage polarization, generation of lipid signalling intermediates and serving as a nutrient depot for mechanistic target of rapamycin activation, each of which can have profound implications in atherosclerosis. Finally, the discovery of the transcription factor transcription factor EB as a mechanism of inducing lysosomal biogenesis can have therapeutic value by reversing lysosomal dysfunction in macrophages.
  
  
  CONCLUSIONS
  Lysosomes are a central organelle in the processing of exogenous and intracellular biomolecules. Together with recent data that implicate the degradation products of lysosomes in modulation of signalling pathways, these organelles truly do lay at a nexus in nutrient sensing and processing. Dissecting the full repertoire of lysosome function and ensuing dysfunction in plaque macrophages is pivotal to our understanding of atherogenesis.
authors.affiliation: aCardiovascular Division, Department of Medicine bDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Sergin
authors.forename: Trent D
authors.initials: TD
authors.lastname: Evans
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D001343:Autophagy; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D001678:Organelle Biogenesis; D010587:Phagocytosis; D059748:Proteolysis