Cargando…

Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency

Farber Disease (FD) is an ultra-rare Lysosomal Storage Disorder caused by deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency manifest a spectrum of symptoms including formation of nodules, painful joints, and a hoarse voice. Classic FD patients will develop histiocytes in o...

Descripción completa

Detalles Bibliográficos
Autores principales: Yu, Fabian P. S., Dworski, Shaalee, Medin, Jeffrey A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789088/
https://www.ncbi.nlm.nih.gov/pubmed/29379059
http://dx.doi.org/10.1038/s41598-018-20052-6
_version_ 1783296201412575232
author Yu, Fabian P. S.
Dworski, Shaalee
Medin, Jeffrey A.
author_facet Yu, Fabian P. S.
Dworski, Shaalee
Medin, Jeffrey A.
author_sort Yu, Fabian P. S.
collection PubMed
description Farber Disease (FD) is an ultra-rare Lysosomal Storage Disorder caused by deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency manifest a spectrum of symptoms including formation of nodules, painful joints, and a hoarse voice. Classic FD patients will develop histiocytes in organs and die in childhood. Monocyte chemotactic protein (MCP-1; CCL2) is significantly elevated in both FD patients and a mouse model we previously generated. Here, to further study MCP-1 in FD, we created an ACDase;MCP-1 double mutant mouse. We show that deletion of MCP-1 reduced leukocytosis, delayed weight loss, and improved lifespan. Reduced inflammation and fibrosis were observed in livers from double mutant animals. Bronchial alveolar lavage fluid analyses revealed a reduction in cellular infiltrates and protein accumulation. Furthermore, reduced sphingolipid accumulation was observed in the lung and liver but not in the brain. The neurological and hematopoietic defects observed in FD mice were maintained. A compensatory cytokine response was found in the double mutants, however, that may contribute to continued signs of inflammation and injury. Taken together, targeting a reduction of MCP-1 opens the door to a better understanding of the mechanistic consequences of ceramide accumulation and may even delay the progression of FD in some organ systems.
format Online
Article
Text
id pubmed-5789088
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-57890882018-02-08 Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency Yu, Fabian P. S. Dworski, Shaalee Medin, Jeffrey A. Sci Rep Article Farber Disease (FD) is an ultra-rare Lysosomal Storage Disorder caused by deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency manifest a spectrum of symptoms including formation of nodules, painful joints, and a hoarse voice. Classic FD patients will develop histiocytes in organs and die in childhood. Monocyte chemotactic protein (MCP-1; CCL2) is significantly elevated in both FD patients and a mouse model we previously generated. Here, to further study MCP-1 in FD, we created an ACDase;MCP-1 double mutant mouse. We show that deletion of MCP-1 reduced leukocytosis, delayed weight loss, and improved lifespan. Reduced inflammation and fibrosis were observed in livers from double mutant animals. Bronchial alveolar lavage fluid analyses revealed a reduction in cellular infiltrates and protein accumulation. Furthermore, reduced sphingolipid accumulation was observed in the lung and liver but not in the brain. The neurological and hematopoietic defects observed in FD mice were maintained. A compensatory cytokine response was found in the double mutants, however, that may contribute to continued signs of inflammation and injury. Taken together, targeting a reduction of MCP-1 opens the door to a better understanding of the mechanistic consequences of ceramide accumulation and may even delay the progression of FD in some organ systems. Nature Publishing Group UK 2018-01-29 /pmc/articles/PMC5789088/ /pubmed/29379059 http://dx.doi.org/10.1038/s41598-018-20052-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yu, Fabian P. S.
Dworski, Shaalee
Medin, Jeffrey A.
Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
title Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
title_full Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
title_fullStr Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
title_full_unstemmed Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
title_short Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
title_sort deletion of mcp-1 impedes pathogenesis of acid ceramidase deficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789088/
https://www.ncbi.nlm.nih.gov/pubmed/29379059
http://dx.doi.org/10.1038/s41598-018-20052-6
work_keys_str_mv AT yufabianps deletionofmcp1impedespathogenesisofacidceramidasedeficiency
AT dworskishaalee deletionofmcp1impedespathogenesisofacidceramidasedeficiency
AT medinjeffreya deletionofmcp1impedespathogenesisofacidceramidasedeficiency