Gene Profile of Myeloid-Derived Suppressive Cells from the Bone Marrow of Lysosomal Acid Lipase Knock-Out Mice

Abstract

BackgroundLysosomal acid lipase (LAL) controls development and homeostasis of myeloid lineage cells. Loss of the lysosomal acid lipase (LAL) function leads to expansion of myeloid-derived suppressive cells (MDSCs) that cause myeloproliferative neoplasm.Methodology/Principal FindingsAffymetrix GeneChip microarray analysis identified detailed intrinsic defects in Ly6G+ myeloid lineage cells of LAL knock-out (lal−/−) mice. Ingenuity Pathway Analysis revealed activation of the mammalian target of rapamycin (mTOR) signaling, which functions as a nutrient/energy/redox sensor, and controls cell growth, cell cycle entry, cell survival, and cell motility. Loss of the LAL function led to major alteration of large GTPase and small GTPase signal transduction pathways. lal−/− Ly6G+ myeloid cells in the bone marrow showed substantial increase of cell proliferation in association with up-regulation of cyclin and cyclin-dependent kinase (cdk) genes. The epigenetic microenvironment was significantly changed due to the increased expression of multiple histone cluster genes, centromere protein genes and chromosome modification genes. Gene expression of bioenergetic pathways, including glycolysis, aerobic glycolysis, mitochondrial oxidative phosphorylation, and respiratory chain proteins, was also increased, while the mitochondrial function was impaired in lal−/− Ly6G+ myeloid cells. The concentration of reactive oxygen species (ROS) was significantly increased accompanied by up-regulation of nitric oxide/ROS production genes in these cells.Conclusions/SignificanceThis comprehensive gene profile study for the first time identifies and defines important gene pathways involved in the myeloid lineage cells towards MDSCs using lal−/− mouse model.

Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal Mice

“…36 Second, Affymetrix GeneChip microarray analysis and Ingenuity Pathway Analysis identified the mammalian target of rapamycin (mTOR) as a major signaling pathway in mediating lal À/À MDSCs malfunctions, including immunosuppression and tumor stimulation. 37 Membrane trafficking causes mTOR to shuttle to lysosomes and regulate mTOR signaling. 38,39 The role of PPARg and mTOR pathways in mediating LAL functions needs to be explored further.…”

Myeloid-Derived Suppressor Cells Are Involved in Lysosomal Acid Lipase Deficiency–Induced Endothelial Cell Dysfunctions

“…MDSCs were isolated as we previously described (17, 20). Briefly, bone marrow cells were isolated from the femurs and tibias of wild-type ( lal +/+ ) and lal −/− mice.…”

“…In ECs, mTOR acts as a regulatory kinase, playing an important role in EC survival, migration, and proliferation (16). We have recently demonstrated that in lal −/− mice, the mTOR pathway was over-activated in bone marrow-derived MDSCs (17). However, it is unknown whether the mTOR pathway is overly activated in lal −/− ECs, and whether over-activation of this pathway is involved in EC dysfunctions.…”

Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

“…In a mouse model, loss of the lysosomal acid lipase function leads to expansion of myeloidderived suppressive cells that cause myeloproliferative Brought to you by | University of Connecticut Authenticated Download Date | 5/31/15 9:15 PM neoplasm. Mice deficient in lysosomal acid lipase displayed a 2.2-fold increase in MK5 transcript levels, suggesting that MK5 may be involved in the myeloid lineage cells toward myeloid-derived suppressive cells (Yan et al , 2012 ). Elevated MK5 levels were observed in prostate cancer, but the biological implication in prostate cancer remains to be determined (Dahlman et al , 2012 ;Whitworth et al , 2012 ).…”