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(American Journal of Pathology. 2006;169:916-926.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051327

Macrophage-Specific Expression of Human Lysosomal Acid Lipase Corrects Inflammation and Pathogenic Phenotypes in lal^–/– Mice

Cong Yan^*, Xuemei Lian, Yuan Li^*, Ying Dai^*, Amanda White, Yulin Qin, Huimin Li, David A. Hume and Hong Du

From The Center for Immunobiology,^* Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; the Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; and the Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell. The downstream metabolites of these compounds serve as hormonal ligands for nuclear receptors and transcription factors. Genetic ablation of the lal gene in the mouse caused malformation of macrophages and inflammation-triggered multiple pathogenic phenotypes in multiple organs. To assess the relationship between macrophages and lal^–/– pathogenic phenotypes, a macrophage-specific doxycycline-inducible transgenic system was generated to induce human LAL (hLAL) expression in the lal^–/– genetic background under control of the 7.2-kb c-fms promoter/intron2 regulatory sequence. Doxycycline-induced hLAL expression in macrophages significantly ameliorated aberrant gene expression, inflammatory cell (neutrophil) influx, and pathogenesis in multiple organs. These studies strongly support that neutral lipid metabolism in macrophages contributes to organ inflammation and pathogenesis.

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