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 -/-) mice. Expression of hLAL in myeloid cells of lal -/- 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 -/- 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 -/- mice reversed CD11b +Gr-1 + myeloid cell suppression of CD4 + T cell proliferation, T cell signaling activation, and lymphokine secretion. Blocking stat3 and NF-κB p65 signaling by small-molecule inhibitors in MDSCs achieved a similar effect. Injection of anti-Gr-1 Ab 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 hematopoietic cell development and balancing immunosuppression and inflammation.
ASJC Scopus subject areas
- Immunology and Allergy