Revised: April 2, 2014
Accepted: June 18, 2014
Published online: July 27, 2014
Processing time: 151 Days and 13.4 Hours
Lysosomal acid lipase (LAL) cleaves cholesteryl esters (CE) and triglycerides (TG) to generate cholesterol and free fatty acid in lysosomes of cells. The downstream metabolic products of fatty acids are ligands for activation of peroxisome proliferator-activated receptor gamma (PPARγ). Accumulation of CEs and TGs is resulted from lack of functional LAL in lysosomes of cells, especially in myeloid cells. One characteristic phenotype in LAL knock-out (lal-/-) mice is systemic elevation of myeloid-derived suppressive cells (MDSCs). MDSCs infiltrate into multiple distal organs, alter T cell development, and suppress T cell proliferation and lymphokine production in lal-/- mice, which lead to severe pathogeneses in multiple organs. The gene transcriptional profile analysis in MDSCs from the bone marrow has identified multiple defects responsible for MDSCs malformation and malfunction in lal-/- mice, including G protein signaling, cell cycles, glycolysis metabolism, mitochondrial bioenergetics, mTOR pathway etc. In a separate gene transcriptional profile analysis in the lung of lal-/- mice, matrix metalloproteinase 12 (MMP12) and apoptosis inhibitor 6 (Api6) are highly overexpressed due to lack of ligand synthesis for PPARγ. PPARγ negatively regulates MMP12 and Api6. Blocking the PPAR signaling by overexpression of a dominant negative PPARγ (dnPPARγ) form, or overexpressing MMP12 or Api6 in myeloid or lung epithelial cells in inducible transgenic mouse models results in elevated MDSCs and inflammation-induced tumorigenesis. These studies demonstrate that LAL and its downstream effectors are critical for MDSCs development, differentiation and malfunction.
Core tip: Neutral lipid metabolism is essential for myeloid cell proliferation and differentiation. This review summarizes the most recent discoveries that lysosomal acid lipase (LAL), an enzyme hydrolysing cholesteryl esters and triglycerides in lysosomes, plays a critical role in myeloid-derived suppressive cells (MDSCs) development, differentiation, and immune suppressive function. Both LAL knock-out and myeloid specific rescue of LAL knock-out mice are used in the studies. Doxycycline-inducible bitransgenic mouse models of LAL downstream genes are also generated to study MDSCs malformation and malfunction. The molecular pathways/mechanisms to connect LAL and MDSCs are characterized by microarray analyses of gene transcriptional profiles.