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Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage

Niemann–Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann–Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the inn...

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Autores principales: Klein, Andrés D., González de la Vega, Javier, Zanlungo, Silvana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139721/
https://www.ncbi.nlm.nih.gov/pubmed/32244854
http://dx.doi.org/10.3390/ijms21062127
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author Klein, Andrés D.
González de la Vega, Javier
Zanlungo, Silvana
author_facet Klein, Andrés D.
González de la Vega, Javier
Zanlungo, Silvana
author_sort Klein, Andrés D.
collection PubMed
description Niemann–Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann–Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann–Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease.
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spelling pubmed-71397212020-04-10 Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage Klein, Andrés D. González de la Vega, Javier Zanlungo, Silvana Int J Mol Sci Article Niemann–Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann–Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann–Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease. MDPI 2020-03-20 /pmc/articles/PMC7139721/ /pubmed/32244854 http://dx.doi.org/10.3390/ijms21062127 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Klein, Andrés D.
González de la Vega, Javier
Zanlungo, Silvana
Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage
title Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage
title_full Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage
title_fullStr Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage
title_full_unstemmed Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage
title_short Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage
title_sort complement component c3 participates in early stages of niemann–pick c mouse liver damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139721/
https://www.ncbi.nlm.nih.gov/pubmed/32244854
http://dx.doi.org/10.3390/ijms21062127
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