Critical Roles of Lysosomal Acid Lipase in Myelopoiesis
Critical Roles of Lysosomal Acid Lipase in Myelopoiesis
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DOI：
10.2353/ajpath.2010.091063
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发表时间：
2010-05-01
影响因子：
6
通讯作者：
Yan, Cong
中科院分区：
文献类型：
--
作者：
Qu, Peng;Shelley, William C.;Yan, Cong
溶酶体酸性脂肪酶（lysosomalacidlipase，LAL）是在溶酶体中裂解胆固醇酯和甘油三酯生成游离脂肪酸和胆固醇的关键酶。小鼠中lal基因（lal（-/-））的基因切除导致巨噬细胞和中性粒细胞的全身性增加，引起多个器官中的严重炎症和发病机制。我们假设lal（-/-）小鼠骨髓细胞的异常生长和分化源于骨髓中祖细胞的生产失调。事实上，lal（-/-）小鼠显示原始（LSK）细胞和粒细胞-巨噬细胞前体（GMP）数量增加。从培养的lal（-/-）骨髓细胞中计数出增加的高增殖潜能集落形成细胞（HPP-CFC），以及显著更多的CFU-GM、CFU-G和CFU-M集落。结果，lal（-/-）小鼠出现显著的骨髓浸润，特别是多个器官中的CD 11b（+）/Gr-1（+）骨髓来源的抑制性细胞。细胞凋亡减少和增殖增加都有助于lal（-/-）髓样细胞中髓样细胞的系统性增加。这些lal（-/-）CD 11b（+）/Gr-1（+）细胞在体外对T细胞增殖和功能具有抑制作用。骨髓嵌合体证实了lal（-/-）小鼠的骨髓增生性疾病主要归因于髓系祖细胞的自主缺陷，尽管lal（-/-）小鼠的造血微环境不支持正常的造血。这些结果提供了证据表明，LAL是造血发育，分化和稳态过程中骨髓生成的重要调节因子。(Am J Pathol 2010，176：2394-2404; DOI：10.2353/ajpath.2010.091063）
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 (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. (Am J Pathol 2010, 176:2394-2404; DOI: 10.2353/ajpath.2010.091063)