Myeloid-Derived Suppressor Cells in Malformation and Malfunction of Lysosomal Acid Lipase Corrects Myeloid-Specific Expression of Human

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 reintroduce human lysosomal acid lipase (hLAL) expression into LAL gene knockout ( lal 2 / 2 ) mice. Expression of hLAL in myeloid cells of lal 2 / 2 mice reversed abnormal myelopoiesis in the bone marrow starting at the granulocyte–monocyte progenitor 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 2 / 2 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 coculture experiments showed that myeloid hLAL expression in lal 2 / 2 mice reversed CD11b + Gr-1 + myeloid cell suppression of CD4 + T cell proliferation, T cell signaling activation, and lymphokine secretion. Blocking stat3 and NF- k B p65 signaling by small-molecule inhibitors in MDSCs achieved a similar effect. Injection of anti–Gr-1 Ab into lal 2 / 2 mice to deplete restored T cell These studies demonstrate that LAL in myeloid cells plays a critical role in