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| Content Provider | PubMed Central |
|---|---|
| Author | Qu, Peng Yan, Cong Blum, Janice S. Kapur, Reuben Du, Hong |
| Abstract | 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. |
| Related Links | http://dx.doi.org/10.4049/jimmunol.1003358 |
| Starting Page | 3854 |
| File Format | |
| ISSN | 15506606 |
| e-ISSN | 15506606 |
| Journal | Journal of immunology (Baltimore, Md. : 1950) |
| Issue Number | 7 |
| Volume Number | 187 |
| Language | English |
| Publisher Date | 2011-10-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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