Critical Roles of Lysosomal Acid Lipase in Myelopoiesis

Abstract

Lysosomal acid lipase (LAL) is a key enzyme that

Signal Transducer and Activator of Transcription 3 (Stat3C) Promotes Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis

“…CD11b ϩ Gr-1 ϩ cells from both lal Ϫ/Ϫ and CCSPrtTA/(tetO) 7 -CMV-Stat3C animal models show similar intrinsic changes, in which activation of intracellular molecules (eg, Stat3, Erk, p38, NF-B) is increased ( Figure 6, A and B). 31 The same observation was made also in AT II epithelial cells in doxycycline-treated CCSP-rtTA/(tetO) 7 -CMV-Stat3C bitransgenic mice ( Figure 6, C and D). These findings indicate that these oncogenic molecules not only participate in AT II epithelial cell to cancerous cell transformation, but also sustain CD11b ϩ Gr-1 ϩ cell expansion.…”

“…This differs from observations in lysosomal acid lipase knockout mice and c-fms-rtTA/(tetO) 7 -CMV-MMP12 bitransgenic mice that cause systemic inflammation and pathogenic phenotypes, as we recently reported, in which CD11b ϩ Ly6G ϩ cells show systemic expansion, including bone marrow, spleen, blood, and lung. 4,31 In those animal models, CD11b ϩ Ly6G ϩ cell expansion is mainly caused by abnormal hematopoietic development, differentiation, and myelopoiesis.…”

Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis

“…3 Blocking cholesterol ester and triglyceride metabolism in LAL-knockout mice (lal Ϫ/Ϫ ) resulted in abnormal myeloid development, differentiation, and homeostasis within the BM. 4 LAL loss led to severe inflammation and pathogenic phenotypes in multiple organs. [5][6][7][8][9] One of manifestations of inflammation in lal Ϫ/Ϫ mice was expansion of myeloid-derived suppressor cells (MDSCs).…”

“…[5][6][7][8][9] One of manifestations of inflammation in lal Ϫ/Ϫ mice was expansion of myeloid-derived suppressor cells (MDSCs). 4 MDSCs are a heterogeneous population of myeloid cells composed of myeloid progenitor cells and immature myeloid cells, which are commonly defined by the markers CD11b (␣M-integrin) and Gr-1 (Ly6-C/G) in the mouse. [10][11][12] MDSCs from lal Ϫ/Ϫ mice displayed strong suppression of T-cell proliferation and function in vitro.…”

“…[10][11][12] MDSCs from lal Ϫ/Ϫ mice displayed strong suppression of T-cell proliferation and function in vitro. 4 Infiltration of MDSCs in lal Ϫ/Ϫ mice impaired T-cell development in the thymus and T-cell maturation in the spleen. 4,13 Myeloidspecific expression of LAL in lal Ϫ/Ϫ mice ameliorated inflammation and tissue pathogenesis.…”