Critical roles of lysosomal acid lipase in myelopoiesis

Peng Qu, William C. Shelley, Mervin C. Yoder, Lingyan Wu, Hong Du, Cong Yan

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Lysosomal acid lipase (LAL) is a key enzyme that cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. Genetic ablation of the lal gene (lal-/-) in mice has resulted in a systemic increase of macrophages and neutrophils, causing severe inflammation and pathogenesis in multiple organs. We hypothesized that aberrant growth and differentiation of myeloid cells in lal-/- mice arises from dysregulated production of progenitor cells in the bone marrow. Indeed, lal -/- mice displayed increased numbers of primitive lin -Sca-1+c-Kit+ (LSK) cells and granulocyte-macrophage precursors (GMP). Increased high proliferative potential colony-forming cells (HPP-CFC) were enumerated from cultured lal-/- bone marrow cells, as were significantly more CFU-GM, CFU-G, and CFU-M colonies. As a consequence, lal-/- mice developed significant myeloid infiltration , particularly with CD11b+/Gr-1+ myeloid-derived suppressive cells in multiple organs. Both decreased apoptosis and increased proliferation contribute to the systemic increase of myeloid cells in lal-/- myeloid cells. These lal-/- CD11b +/Gr-1+ cells displayed suppressive activity on T cell proliferation and function in vitro. Bone marrow chimeras confirmed that the myeloproliferative disorder in lal-/- mice was primarily attributable to autonomous defects in myeloid progenitor cells , although the hematopoietic microenvironment in the lal-/- mice did not support hematopoiesis normally. These results provide evidence that LAL is an important regulator of myelopoiesis during hematopoietic development, differentiation, and homeostasis.

Original languageEnglish (US)
Pages (from-to)2394-2404
Number of pages11
JournalAmerican Journal of Pathology
Volume176
Issue number5
DOIs
StatePublished - May 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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