Critical Roles of Lysosomal Acid Lipase in Myelopoiesis

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.Hematopoietic stem cells possess the capacity for self-renewal and the ability to differentiate into all lineages of mature hematopoietic cells.¹ The production of mature blood cells requires the sequential proliferation and differentiation of hematopoietic stem cells through a successive series of increasingly lineage-restricted intermediate progenitors including common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), and the megakaryocyte-erythroid progenitors (MEPs).² Because bone marrow-derived myeloid cells and lymphoid cells are effectors of inflammation and tissue remodeling in many organs, elucidating the molecular mechanisms governing hematopoiesis during the process of lineage commitment and lineage-specific expansion is critical for understanding inflammation-induced tissue damage and disease formation.Lysosomal acid lipase (LAL) is a lysosomal hydrolase. It hydrolyzes cholesteryl esters and triglycerides in the lysosome of cells to generate free cholesterol and free fatty acids. Ablating LAL (lal^−/−) in mice led to severe pathogenic phenotypes in multiple organs, including the adult liver, lung, spleen, adrenal glands, and small intestine.^3,4,5 These pathogenic changes in lal^−/− mice were highly associated with infiltration of macrophages and neutrophils,^3,6,7 suggesting that LAL plays a critical role in regulating the development, differentiation, and/or proliferation of myeloid lineage cells. This was supported by an observation that genetic intercross of a conditional transgenic mouse model in which LAL was specifically expressed in myeloid lineage cells with lal^−/− mice led to amelioration of the systemic inflammation and tissue pathogenesis.⁶To fully understand the dysregulated production of myeloid cells that are involved in lal^−/− disease formation, it is essential to elucidate the role of LAL in hematopoiesis. Our present results have revealed that LAL deficiency causes hematopoietic cell–intrinsic defects leading to profound blood phenotypes, especially an enhancement in CD11b⁺/Gr-1⁺ myeloid cells. LAL deletion in mice altered the frequency and the number of primitive IL7R⁻Lin⁻Sca-1⁺c-Kit⁺ (LSK), CMP, GMP, and MEP populations in the bone marrow and changed myeloid cell distribution in the bone marrow, peripheral blood, spleen, and distal organs (eg, lung). When LAL deficient hematopoietic progenitor cells were assessed in clonogenic assays, significant increases in the numbers of myeloid colony forming cells (CFCs) were enumerated. Both hematopoietic progenitor cell defects and a microenvironmental change in lal^−/− mice contributed to the above phenotype in bone marrow transplantation studies. These results demonstrate that neutral lipids and lipid mediators play important roles in normal myelopoiesis and contribute to abnormal inflammatory responses and disease formation in lal^−/− mice.