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Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency. Sci Rep 2018 Jan 29;8(1):1808

Date

01/31/2018

Pubmed ID

29379059

Pubmed Central ID

PMC5789088

DOI

10.1038/s41598-018-20052-6

Scopus ID

2-s2.0-85041374187 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

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.

Author List

Yu FPS, Dworski S, Medin JA

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acid Ceramidase
Animals
Bronchoalveolar Lavage Fluid
Chemokine CCL2
Cytokines
Farber Lipogranulomatosis
Female
Fibrosis
Inflammation
Leukocytosis
Liver
Lung
Male
Mice
Mice, Knockout
Sequence Deletion