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.
Highlights
The mouse model of Farber Disease (FD) that we developed demonstrates a unique cytokine profile that includes dramatically higher levels of MCP-1 in plasma[6]
We previously demonstrated that MCP-1 levels are reduced in FD patient plasma post-BMT6
Deletion of MCP-1 improves the course of FD
Summary
The mouse model of FD that we developed demonstrates a unique cytokine profile that includes dramatically higher levels of MCP-1 in plasma[6]. MCP-1 is a potent chemoattractant that is responsible for the recruitment of monocytes It is a member of the C-C chemokine subfamily and functions by binding to its G-protein coupled receptor: chemokine receptor 2 (CCR2). Numerous FD case reports have demonstrated that histiocytic infiltration is present in many tissues and that plasma chitotriosidase is significantly elevated[3,11] This inflammatory phenotype is reflected in our Asah1P361R/P361R mouse, which displays macrophage and neutrophil infiltration in various tissues and organs[4,12]. Several case reports have demonstrated that BMT reduced the number and size of subcutaneous nodules and decreased joint pain in patients with FD14,15 Along these lines, we previously demonstrated that MCP-1 levels are reduced in FD patient plasma post-BMT6. This is an important insight into the pathogenesis of this disorder and opens the door to a whole new line of therapy
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