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Global gene expression profiles and the progression of pro- and anti-inflammatory pathways in mouse models

ABSTRACT: Gaucher Disease (GD) is caused by defective glucocerebrosidase (GCase) activity and the consequent accumulation of its substrate, glucosylceramide (GC). This excess of accumulation of GC leads to broad functional impairments in multiple organs, but the pathogenic pathways leading to lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal function is obscure. To understand the molecular pathogenesis of GD, developmental global gene expression was conducted by microarray analyses of total mRNAs from lung and liver of two distinct GCase point-mutated mice (V394L/V394L and D409V/null) and genetic background matched wild-type controls. INFg regulated pro-inflammatory and IL-4 regulated anti-inflammatory cytokine/mediator network were constructed in the lung and liver of GCase mutant mice. Progressive alterations of the INFg and IL-4 pathways were similar, but to different degrees, in visceral tissues from the two different GCase mutated mice. These analyses implicate IFNg regulated pro-inflammatory and IL-4 regulated anti-inflammatory networks in the differential pathophysiological progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE23408 | GEO | 2011/08/02

SECONDARY ACCESSION(S): PRJNA131061

REPOSITORIES: GEO

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Project description:In non-neuronopathic type 1 Gaucher disease (GD1) mutations in GBA1 gene results in deficiency of glucocerebrosidase and the accumulation of glucocerebroside in lysosomes of mononuclear phagocytes. The metabolic defect leads to a complex phenotype involving the viscera, the bone marrow and the skeleton. However the prevailing macrophage-centric view of the disease does not explain emerging aspects of the disease such as hematological malignancies, autoimmune diathesis, ParkinsonM-bM-^@M-^Ys disease and osteoporosis poorly responsive to macrophage targeted enzyme therapy or anti-resorptive therapies. We developed a conditional KO mouse model of GD1 to delineate cells and pathways in GD1. By targeting the cells of the hematopoetic and mesenchymal cell lineages through an Mx1 promoter, we recapitulated human GD1. We show that, in addition to significant visceral and hematologic disease, GD1 mice show profound osteopenia due to a bone formation defect. Cytokine measurements, microarray analysis and cellular immunophenotyping together point to widespread dysfunction of macrophages and other immune cells together with a striking abnormality in thymic T-cell development. Our study provides the first direct evidence for the involvement of cell lineages other than mononuclear phagocytes, most notably osteoblasts and T cells, in the pathophysiology of the clinical spectrum of type 1 GD. These findings have important implications for treatment of GD1. We hypothesize that regulation of gene expression is different in Gaucher disease compared with the normal controls. This difference may even be evident in the different stages of this disease. In order to gain insight to the genes that are potentially involved in the development of Gaucher disease in its different clinical stages, exon-array is chosen for this genome-wide association studies. Mouse liver and spleen samples from normal control, GD with moderate to severe splenomegaly/hepatomegaly, together nine samples were chosen. The goal is to find out genes of which the expression may relate to the GD or the severity of GD and thus help identify genetic modifier genes that may contribute to the onset and development of Gaucher disease.

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Global gene expression profiles and the progression of pro- and anti-inflammatory pathways in mouse models

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