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. 2002 May;109(9):1215-21.
doi: 10.1172/JCI14530.

Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage

Hiroki Mizukami  1 , Yide Mi, Ryuichi Wada, Mari Kono, Tadashi Yamashita, Yujing Liu, Norbert Werth, Roger Sandhoff, Konrad Sandhoff, Richard L Proia
Affiliations

Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage

Hiroki Mizukami et al. J Clin Invest. 2002 May.

Abstract

Gaucher disease, the most common lysosomal storage disease, is caused by a deficiency of glucocerebrosidase resulting in the impairment of glucosylceramide degradation. The hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause many of the clinical manifestations of the disease. We have developed adult mice carrying the Gaucher disease L444P point mutation in the glucocerebrosidase (Gba) gene and exhibiting a partial enzyme deficiency. The mutant mice demonstrate multisystem inflammation, including evidence of B cell hyperproliferation, an aspect of the disease found in some patients. However, the mutant mice do not accumulate large amounts of glucosylceramide or exhibit classic Gaucher cells in tissues.

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Figures

Figure 1
Figure 1
Degradation and synthesis of glucosylceramide, and derivation of GbaL444P/L444P mice. (a) Pathway of glucosylceramide degradation and synthesis. Glucosylceramide synthase is encoded by the Ugcg gene. Glucocerebrosidase (known also as acid β-glucosidase) is encoded by the Gba gene. (b) Breeding scheme to derive adult GbaL444P/L444 mice. As described in Methods, heterozygous mice with the L444P mutation in the Gba gene were cross-bred with mice carrying a disrupted Ugcg allele (UgcgKO) to eventually obtain adult mice with the genotype GbaL444P/L444PUgcg+/KO. These double mutant mice were intercrossed to obtain adult mice with the genotype GbaL444P/L444PUgcg+/+.
Figure 2
Figure 2
Growth, enzyme levels, organ weights, and lipid analysis of GbaL444P/L444P mice. (a) Body weights were determined from 12 to 120 days of age. Filled circles represent the weights of GbaL444P/L444P mice; open squares represent the weights of wild-type mice. Results are means ± SEM for three to seven male mice at each age. *P < 0.05, **P < 0.01. (b) Acid β-glucosidase activity in brain, spleen, liver, and lung of mutant (L444P) and wild-type (WT) mice. Activity is expressed as nanomoles of substrate cleaved per milligrams of protein per hour. Results are means ± SEM for three mice each. (c) Left panel: Spleen weights of mutant (L444P) and wild-type (WT) mice. Results are means ± SEM for 23–24 mice. *P < 0.001. Right panel: Ratio of liver to body weight of mutant (L444P) and wild-type (WT) mice. *P < 0.01. Results are means ± SEM for 21–22 mice. (d) Thin-layer chromatography of neutral lipid fraction from liver, spleen, and brain of 2-month-old mutant (L444P) and wild-type (WT) mice. The migration positions of glucosylceramide (GlcCer), galactosylceramide (GalCer), and lactosylceramide (LacCer) are shown.
Figure 3
Figure 3
Inflammatory reaction in the liver of GbaL444P/L444P mice. (a) Inflammatory foci were scattered in the liver of a 2-month-old mutant mouse (arrows). (b) Higher magnification of an inflammatory area. Note the apoptotic hepatocyte in the inflammatory area (arrow). (c) Immunostaining with F4/80 antibody to visualize ramified Kupffer cells in wild-type liver sections. (d) In mutant liver, the F4/80–positive Kupffer cells were amoeboid and swollen. (e) TUNEL-positive, apoptotic nuclei (arrows) were distinguished in the inflammatory lesion of the mutant mouse. (f) TNF-α mRNA expression in the liver of mutant and wild-type mice. *P < 0.001. Results are means ± SEM for four to seven mice each. Bars = 50 μm.
Figure 4
Figure 4
Abnormal macrophages with lipofuscin granules and tubular structures. Inset; liver section from a 7-month-old mutant mouse showing multinucleated macrophages (arrows) containing abundant brown granules in their cytoplasm. Bar = 50 μm. Main portion: Electron microscopy revealed that these cells contain lipofuscin granules (L) and abundant parallel and twisted tubular structures (arrows) in their cytoplasm. Bar = 0.25 μm.
Figure 5
Figure 5
Pathology in lung and skin of GbaL444P/L444P mice. (a) Lung of mutant mice showed scattered inflammatory cell aggregations (arrows) in the mesenchyme. (b) Lung of wild-type mice showed no signs of inflammation. (c and d) Skin sections of mutant (c) and control mice (d). Stratum corneum (SC) and epidermis (ED) of mutant mice were thicker than those of wild-type mice. Inflammatory cell infiltration was distinguished in upper dermis (DER) of mutant mice (arrows). Bars = 50 μm.
Figure 6
Figure 6
Lymph node hypertrophy in the GbaL444P/L444P mice. (a) Cervical, axillary, inguinal, and mesenteric lymph nodes were removed from a 2-month-old wild-type and a 2-month-old GbaL444P/L444P mouse. The lymph nodes of mutant mice (b) showed follicular hyperplasia and dilated parafollicular zones compared with the lymph nodes of control mice (c). Immunostaining for κ light chain showed large numbers of positive cells in the lymph nodes of the mutant mice (d) compared with wild-type mice (e). Arrows point out a few of the positive cells. (f) Plasmacytosis in the cervical lymph node of a 9-month-old mutant mouse. Arrows point out a few of the abundant large plasma cells. Bars = 50 μm. (g) Left panel: IL-1β mRNA expression in the cervical lymph nodes of mutant (L444P) and wild-type mice. Results are means ± SEM for six mice. *P < 0.05. Right panel: Serum IgG levels in mutant (L444P) and wild-type mice. Results are means ± SEM for five mice.
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