Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function

Qu, Peng; Du, Hong; Wilkes, David S.; Yan, Cong

doi:10.2353/ajpath.2009.080562

Cited by 51 publications

(76 citation statements)

References 17 publications

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“…ϩ Lin Ϫ Sca-1 int c-Kit int ) frequency and number were significantly decreased, consistent with our recent findings on lymphocyte development and maturation in lal Ϫ/Ϫ mice 9 and with the present observations of a progenitor production skewing toward the myeloid lineage. To assess whether increased CMP and GMP in lal Ϫ/Ϫ mice were attributable to cell proliferation, lal ϩ/ϩ and lal Ϫ/Ϫ mice were injected intraperitoneally with BrdU.…”

Section: Effect Of Lal Deficiency On Hematopoietic Progenitor Populatsupporting

confidence: 93%

“…As we reported previously, LAL deficiency causes malformation and malfunction in many tissues, including the adult liver, lung, spleen, thymus, adrenal glands, and small intestine. [3][4][5][6]9 These environmental changes are able to influence myelopoiesis. For example, the Affymetrix GeneChip microarray study identified overexpression of matrix metalloproteinase 12 (MMP12) gene in the lung.…”

Section: Discussionmentioning

confidence: 99%

“…This directly affected lymphopoiesis in lal Ϫ/Ϫ mice as we recently reported. 9 In lal Ϫ/Ϫ mice, LAL deficiency led to abnormal organization of the thymus and spleen structures. LAL deficiency impaired progression of T cell development in the thymus and retarded maturation of peripheral T cells.…”

Section: Discussionmentioning

confidence: 99%

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Critical Roles of Lysosomal Acid Lipase in Myelopoiesis

Shelley

Yoder

et al. 2010

The American Journal of Pathology

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Section: Effect Of Lal Deficiency On Hematopoietic Progenitor Populatsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Critical Roles of Lysosomal Acid Lipase in Myelopoiesis

Shelley

Yoder

et al. 2010

The American Journal of Pathology

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“…These effects can, at least in part, be attributed to the antiproliferative effects of the accumulated lipids (41). Similar immune phenotypes have been described in other inherited lipidosis (43,44). Thus, on a broader note, the studies underscore the importance of defining the role of aberrant immunity and the interactions between lipids and immune cells in genetic lipidosis and reversal of immune dysregulation as an additional therapeutic target (45).…”

Section: Discussionmentioning

confidence: 58%

Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Inherited deficiency of acid β-glucosidase (GCase) due to biallelic mutations in the GBA (glucosidase, β, acid) gene causes the classic manifestations of Gaucher disease (GD) involving the viscera, the skeleton, and the lungs. Clinical observations point to immune defects in GD beyond the accumulation of activated macrophages engorged with lysosomal glucosylceramide. Here, we show a plethora of immune cell aberrations in mice in which the GBA gene is deleted conditionally in hematopoietic stem cells (HSCs). The thymus exhibited the earliest and most striking alterations reminiscent of impaired T-cell maturation, aberrant B-cell recruitment, enhanced antigen presentation, and impaired egress of mature thymocytes. These changes correlated strongly with disease severity. In contrast to the profound defects in the thymus, there were only limited cellular defects in peripheral lymphoid organs, mainly restricted to mice with severe disease. The cellular changes in GCase deficiency were accompanied by elevated T-helper (Th)1 and Th2 cytokines that also tracked with disease severity. Finally, the proliferation of GCase-deficient HSCs was inhibited significantly by both GL1 and Lyso-GL1, suggesting that the “supply” of early thymic progenitors from bone marrow may, in fact, be reduced in GBA deficiency. The results not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregulation through the accumulation of substrates.

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“…12 Cells from various organs in fluorescence-activated cell sorting buffer were stained with cell surface markers. Anti-CD4, anti-CD8, anti-CD11b, and anti-Ly6G were purchased from eBioscience (San Diego, CA).…”

Section: Flow Cytometrymentioning

confidence: 99%

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

et al. 2011

The American Journal of Pathology

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We have previously reported that persistent activation of the Stat3 signaling pathway, by overexpressing constitutively active Stat3C, in lung alveolar type II (AT II) epithelial cells directly induces spontaneous bronchioalveolar adenocarcinoma in CCSP-rtTA/(tetO) 7 -Stat3C bitransgenic mice. 1 The process is initiated by synthesis and induction of proinflammatory cytokines and chemokines in AT II epithelial cells, triggering heightened levels of inflammatory cell infiltration. Subsequent studies showed that persistent activation of Stat3 in AT II epithelial cells is a common phenomenon in inflammation-induced lung tumor animal models, as demonstrated by matrix metalloproteinase 12 (MMP12) and apoptosis inhibitor 6 (Api6) overexpression bitransgenic mouse models. 2-4 These findings suggested that Stat3 plays a critical role in mediating inflammation-induced lung adenocarcinoma formation. In a clinical setting, the expression of Stat3 and the genes it induces are increased in human lung adenocarcinoma and in chronic obstructive pulmonary disease, a disease similar in pulmonary impairment to lung cancer. 5 Both diseases are common in human smokers. A knockin mouse model also shows the enhanced tumorigenic power of the Stat3C molecule in mammary tumors. 6

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Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function

Cited by 51 publications

References 17 publications

Critical Roles of Lysosomal Acid Lipase in Myelopoiesis

Critical Roles of Lysosomal Acid Lipase in Myelopoiesis

Gaucher disease geneGBAfunctions in immune regulation

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

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