Abstract
Niemann-Pick type C1 (NPC1) disease is a progressive lysosomal storage disorder caused by mutations of the NPC1 gene. While neurodegeneration is the most severe symptom, a large proportion of NPC1 patients also present with splenomegaly, which has been attributed to cholesterol and glycosphingolipid accumulation in late endosomes and lysosomes. However, recent data also reveal an increase in the inflammatory monocyte subset in the Npc1nih mouse model expressing an Npc1 null allele. We evaluated the contribution of hematopoietic cells to splenomegaly in NPC1 disease under conditions of hypercholesterolemia. We transplanted Npc1nih (Npc1 null mutation) or Npc1wt bone marrow (BM) into Ldlr−/− mice and fed these mice a cholesterol-rich Western-type diet. At 9 weeks after BM transplant, on a chow diet, the Npc1 null mutation increased plasma granulocyte-colony stimulating factor (G-CSF) by 2-fold and caused mild neutrophilia. At 18 weeks after BM transplant, including 9 weeks of Western-type diet feeding, the Npc1 mutation increased G-csf mRNA levels by ∼5-fold in splenic monocytes/macrophages accompanied by a ∼4-fold increase in splenic neutrophils compared with controls. We also observed ∼5-fold increased long-term and short-term hematopoietic stem cells (HSCs) in the spleen, and a ∼30–75% decrease of these populations in BM, reflecting HSC mobilization, presumably downstream of elevated G-CSF. In line with these data, four patients with NPC1 disease showed higher plasma G-CSF compared with age-matched and gender-matched healthy controls. In conclusion, we show elevated G-CSF levels and HSC mobilization in the setting of an Npc1 null mutation and propose that this contributes to splenomegaly in patients with NPC1 disease.
Highlights
Niemann-Pick type C (NPC) disease is a progressive lysosomal storage disorder with an estimated incidence of 1:100,000–120,000 among newborns [1, 2], caused by an autosomal recessive mutation in the Niemann-Pick type C1 (NPC1) (95% of the cases; Online Mendelian Inheritance in Man no.: 257220) or NPC2 gene
At 5 weeks after bone marrow transplantation (BMT), when mice were fed a chow diet, we observed no effects of hematopoietic Npc1 mutation on total white blood cell (WBC) counts (Fig. 1A), suggesting no difference in bone marrow (BM) reconstitution between the groups of mice, which was similar to a previous study using the exact same approach [28]
Hematopoietic Npc1 loss-of-function did not affect total blood monocytes in Ldlr−/− mice but decreased Ly6Clo monocytes by ∼55% and increased proinflammatory Ly6Chi monocytes by ∼38% and blood neutrophils by ∼41% (Fig. 1B, D)
Summary
Niemann-Pick type C (NPC) disease is a progressive lysosomal storage disorder with an estimated incidence of 1:100,000–120,000 among newborns [1, 2], caused by an autosomal recessive mutation in the NPC1 (95% of the cases; Online Mendelian Inheritance in Man no.: 257220) or NPC2 gene. While accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes of macrophages with Npc loss-of-function may contribute to splenomegaly [19, 20], the exact cause for this phenotype is unknown. Extramedullary hematopoiesis is the result of hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow (BM) to liver and/or spleen As a consequence, these organs resume their fetal hematopoietic function, reflected by stem cell proliferation and production of monocytes and neutrophils, which causes hepatosplenomegaly [22, 23]. Our previous studies have shown that deficiency of the cholesterol transporters ABCA1 and ABCG1 in monocytes/macrophages, causing plasma membrane and lysosomal cholesterol accumulation, increases HSPC mobilization and plasma G-CSF [25, 26]. We used plasma from patients with NPC1 missense mutations to assess human relevance
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