Pneumococcal Immunization Reduces Neurological and Hepatic Symptoms in a Mouse Model for Niemann-Pick Type C1 Disease

Houben, Tom; Reis, Inês Magro dos; Oligschlaeger, Yvonne; Steinbusch, H.W.M.; Gijbels, Marion J.J.; Hendrikx, Tim; Binder, Christoph J.; Cassiman, David; Westerterp, Marit; Prickaerts, Jos; Shiri-Sverdlov, Ronit

doi:10.3389/fimmu.2018.03089

Cited by 10 publications

(8 citation statements)

References 74 publications

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“…Of note, unlike stanols, phytosterol molecules are prone to oxidation (49,50) and may therefore have pro-inflammatory effects if consumed in high amounts. Given the importance of inflammation in NPC1 disease burden (30,51,52), phytosterol supplementation should thus be regarded with caution. ) and antiinflammatory ( LyC6 low ) monocytes, as well as cytotoxic ( CD8 + ) and helper T-cells (CD4 + ) were measured by FACS analysis on weeks 3 and 5 of the study, when mice were 35 and 49 days old.…”

Section: Discussionmentioning

confidence: 99%

Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease

Reis

Houben

Oligschläger

et al. 2020

Journal of Lipid Research

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Niemann-Pick type C (NPC)1 disease is a rare genetic condition in which the function of the lysosomal cholesterol transporter NPC1 protein is impaired. Consequently, sphingolipids and cholesterol accumulate in lysosomes of all tissues, triggering a cascade of pathological events that culminate in severe systemic and neurological symptoms. Lysosomal cholesterol accumulation is also a key factor in the development of atherosclerosis and NASH. In these two metabolic diseases, the administration of plant stanol esters has been shown to ameliorate cellular cholesterol accumulation and inflammation. Given the overlap of pathological mechanisms among atherosclerosis, NASH, and NPC1 disease, we sought to investigate whether dietary supplementation with plant stanol esters improves the peripheral features of NPC1 disease. To this end, we used an NPC1 murine model featuring a Npc1-null allele (Npc1nih), creating a dysfunctional NPC1 protein. Npc1nih mice were fed a 2% or 6% plant stanol ester-enriched diet over the course of 5 weeks. During this period, hepatic and blood lipid and inflammatory profiles were assessed. Npc1nih mice fed the plant stanol-enriched diet exhibited lower hepatic cholesterol accumulation, damage, and inflammation than regular chow-fed Npc1nih mice. Moreover, plant stanol consumption shifted circulating T-cells and monocytes in particular toward an anti-inflammatory profile. Overall, these effects were stronger following dietary supplementation with 6% stanols, suggesting a dose-dependent effect. The findings of our study highlight the potential use of plant stanols as an affordable complementary means to ameliorate disorders in hepatic and blood lipid metabolism and reduce inflammation in NPC1 disease.

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Section: Discussionmentioning

confidence: 99%

Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease

Reis

Houben

Oligschläger

et al. 2020

Journal of Lipid Research

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“…Six-week-old bone marrow from Npc1 nih and Npc1 wt mice donors were derived from heterozygous founders of a C57BL/6 genetic background. The genotype of Npc1 nih and Npc1 wt mice was determined as previously described [ 10 ]. On the day of bone marrow transplant, Npc1 nih and Npc1 wt littermates were sacrificed via CO 2 inhalation and their bone marrows were isolated.…”

Section: Methodsmentioning

confidence: 99%

“…Biomedicines 2021, 9, x FOR PEER REVIEW 3 of 14 and Npc1 wt mice was determined as previously described [10]. On the day of bone marrow transplant, Npc1 nih and Npc1 wt littermates were sacrificed via CO2 inhalation and their bone marrows were isolated.…”

Section: Mice Bone Marrow Transplant and Dietmentioning

confidence: 99%

Anti-Inflammatory Effects of Dietary Plant Stanol Supplementation Are Largely Dependent on the Intake of Cholesterol in a Mouse Model of Metabolic Inflammation

et al. 2021

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The prevalence of metabolic disorders characterized by chronic inflammation has been on a sharp rise for decades. As such, tools that address metabolic and inflammatory dysregulation are of great importance. Plant stanols are well-known for reducing intestinal cholesterol absorption and may also have direct anti-inflammatory effects. In this study, our aim was to investigate to what extent the benefits of dietary plant stanol supplementation depend on dietary cholesterol intake in an experimental mouse model for cholesterol-induced metabolic inflammation. Here, we used Ldlr−/− mice transplanted with Npc1nih-derived bone marrow, featuring feature bone marrow-derived immune cells characterized by chronic inflammation induced by lysosomal lipid accumulation. Npc1nih- and Npc1wt-transplanted mice were placed on either a high fat, high cholesterol (HFC) or on a chow diet low in cholesterol, with or without 2% plant stanols supplementation. At the end of the study, the metabolic and inflammatory status of the mice was analyzed. Plant stanol supplementation to the HFC diet reduced liver cholesterol levels and improved lipid metabolism and liver inflammation, particularly in Npc1nih-tp mice. In contrast, plant stanol supplementation to the chow diet did not significantly improve the aforementioned parameters, though similar reductive trends to those in the HFC diet setting were observed regarding liver cholesterol accumulation and liver inflammatory markers. The effects of dietary plant stanol supplementation on dietary cholesterol-induced inflammation are largely dependent on dietary cholesterol intake. Future research should verify whether other models of metabolic inflammation exhibit similar stanol-related effects on inflammation.

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“…Six weeks old bone marrow donors Npc1 nih and Npc1 wt mice were derived from heterozygous founders of a C57BL/6 genetic background. Genotype of Npc1 nih and Npc1 wt mice was determined as previously described ( 23 ). On the day of the bone marrow transplant, Npc1 nih and Npc1 wt littermates were sacrificed via CO 2 inhalation and their bone marrows were isolated.…”

Section: Methodsmentioning

confidence: 99%

Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment

et al. 2021

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Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.

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Pneumococcal Immunization Reduces Neurological and Hepatic Symptoms in a Mouse Model for Niemann-Pick Type C1 Disease

Cited by 10 publications

References 74 publications

Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease

Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease

Anti-Inflammatory Effects of Dietary Plant Stanol Supplementation Are Largely Dependent on the Intake of Cholesterol in a Mouse Model of Metabolic Inflammation

Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment

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