Myeloid-specific expression of human lysosomal acid lipase corrects malformation and malfunction of myeloid-derived suppressor cells in lal-/- mice.
Myeloid-specific expression of human lysosomal acid lipase corrects malformation and malfunction of myeloid-derived suppressor cells in lal-/- mice.
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DOI：
10.4049/jimmunol.1003358
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发表时间：
2011-10-01
期刊：
影响因子：
--
通讯作者：
Du H
中科院分区：
文献类型：
--
作者：
Qu P;Yan C;Blum JS;Kapur R;Du H
溶酶体酸性脂肪酶（LAL）裂解胆固醇酯和甘油三酯，在溶酶体中产生游离脂肪酸和胆固醇。LAL缺陷导致CD 11b +GR-1+未成熟髓样细胞扩增、T细胞损失和T细胞功能受损。为了测试骨髓细胞LAL如何控制骨髓生成和淋巴生成，使用骨髓特异性多西环素诱导型转基因系统将人LAL（hLAL）表达重新引入LAL基因敲除（lal−/−）小鼠中。在lal−/−小鼠的骨髓细胞中表达hLAL逆转了骨髓中从粒细胞-巨噬细胞前体（GMP）阶段开始的异常骨髓生成，并减少了骨髓源性抑制细胞（MDSC）的全身扩增。髓样hLAL表达抑制lal−/−小鼠CD 11b +GR-1+细胞中活性氧的产生和脱氢酶的表达。在这些小鼠中，胸腺和脾脏的结构组织部分恢复与CD 11b +GR-1+细胞浸润减少相关。在胸腺中，髓样细胞LAL的重建恢复了双阴性DN 3期胸腺细胞的发育。髓样细胞LAL表达改善外周血T细胞的增殖和功能。体外共培养实验表明，在lal−/−小鼠中髓样hLAL表达逆转了CD 11b +GR-1+髓样细胞对CD 4 + T细胞增殖、T细胞信号传导激活和淋巴因子分泌的抑制。在MDSC中通过小分子抑制剂阻断Stat 3和NFκB p65信号传导达到类似的效果。将抗Gr-1抗体注射到lal−/−小鼠中以消耗MDSC，恢复了T细胞增殖。这些研究表明，髓系细胞中的LAL在维持正常造血细胞发育和平衡免疫抑制和炎症中起关键作用。
Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. LAL deficiency causes expansion of CD11b+GR-1+ immature myeloid cells, loss of T cells and impairment of T cell function. To test how myeloid cell LAL controls myelopoiesis and lymphopoiesis, a myeloid-specific doxycycline-inducible transgenic system was used to re-introduce human LAL (hLAL) expression into LAL gene knock-out (lal−/−)mice. Expression of hLAL in myeloid cells of lal−/− mice reversed abnormal myelopoiesis in the bone marrow starting at the granulocyte-macrophage precursors (GMP) stage and reduced systemic expansion of myeloid-derived suppressor cells (MDSCs). Myeloid hLAL expression inhibited reactive oxygen species production and arginase expression in CD11b+GR-1+ cells of lal−/− mice. Structural organization of the thymus and spleen was partially restored in association with reduced infiltration of CD11b+GR-1+ cells in these mice. In the thymus, reconstitution of myeloid cell LAL restored development of thymocytes at the double-negative DN3 stage. Myeloid cell LAL expression improved the proliferation and function of peripheral T cells. In vitro co-culture experiments showed that myeloid hLAL expression in lal−/− mice reversed CD11b+GR-1+ myeloid cell suppression of CD4+ T cell proliferation, T cell signaling activation, and lymphokine secretion. Blocking Stat3 and NFκB p65 signaling by small molecule inhibitors in MDSCs achieved the similar effect. Injection of anti-Gr-1 antibody into lal−/− mice to deplete MDSCs restored T cell proliferation. These studies demonstrate that LAL in myeloid cells plays a critical role in maintaining normal hematopietic cell development and balancing immunosuppression and inflammation.
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