Acid Ceramidase Deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy

Abstract

Acid Ceramidase Deficiency (Farber disease, FD) is an ultra-rare Lysosomal Storage Disorder that is poorly understood and often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Hallmarks of FD are accumulation of ceramides, widespread macrophage infiltration, splenomegaly, and lymphocytosis. The cytokines involved in this abnormal hematopoietic state are unknown. There are dozens of ceramide species and derivatives, but the specific ones that accumulate in FD have not been investigated. We used a multiplex assay to analyze cytokines and mass spectrometry to analyze ceramides in plasma from patients and mice with FD, controls, Farber patients treated by hematopoietic stem cell transplantation (HSCT), JIA patients, and patients with Gaucher disease. KC, MIP-1α, and MCP-1 were sequentially upregulated in plasma from FD mice. MCP-1, IL-10, IL-6, IL-12, and VEGF levels were elevated in plasma from Farber patients but not in control or JIA patients. C16-Ceramide (C16-Cer) and dhC16-Cer were upregulated in plasma from FD mice. a-OH-C18-Cer, dhC12-Cer, dhC24:1-Cer, and C22:1-Cer-1P accumulated in plasma from patients with FD. Most cytokines and only a-OH-C18-Cer returned to baseline levels in HSCT-treated Farber patients. Sphingosines were not altered. Chitotriosidase activity was also relatively low. A unique cytokine and ceramide profile was seen in the plasma of Farber patients that was not observed in plasma from HSCT-treated Farber patients, JIA patients, or Gaucher patients. The cytokine profile can potentially be used to prevent misdiagnosis of Farber as JIA and to monitor the response to treatment. Further understanding of why these signaling molecules and lipids are elevated can lead to better understanding of the etiology and pathophysiology of FD and inform development of future treatments.

Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates

“…Previous studies by other groups have indicated that neither the acid ceramidase subtype (30), nor the neutral ceramidase subtype (31) contributes to blood SPH and S1P formation. Our previous study demonstrated that the alkaline ceramidase family is important for the maintenance of high blood levels of S1P in mice (32), but which member in the alkaline ceramidase family plays such a role was unknown.…”

“…These studies suggest that, in the alkaline ceramidase family, ACER2 is the only member that plays a role in maintaining high blood levels of S1P in mice via the generation of its precursor, SPH. Previous studies have shown that knocking out Asah1 (30) or Asah2 (31) does not alter blood SPH and S1P levels in mice, and it remains unclear whether the lack of change in the blood levels of SPH and S1P in Asah1‐ or Asah2 ‐deficient mice is a result of a compensatory effect by ACER2. If not, the remainder of the blood S1P precursor, SPH, in Acer2 −/− mice either comes from diet or is generated via an unidentified metabolic pathway.…”

“…1). Patients who are deficient in the acid ceramidase gene ( ASAH1 ) have plasma SPH and S1P levels that are similar to those of healthy individuals (30), and deficiency in the acid ceramidase gene ( Asah1 ) does not affect blood SPH and S1P levels in mice (30). Mice that are deficient in the neutral ceramidase gene ( Asah2 ) have plasma S1P levels that are similar to those of WT mice (31).…”

Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment

“…The opposite phenotype of ceramidase KO models in intestinal inflammation is likely a result of different cellular and tissue localization that regulate different pools of ceramide (25). Although AC has been implicated in immune regulation in cellular and animal models, its function in intestinal inflammation has not yet been investigated (28, 29, 31, 32). In this study, we demonstrate elevated expression of AC in colitis and in murine DSS‐induced colitis (Fig.…”

“…Here, we initially find increased levels of AC expression in the colon lamina propria of human and murine colitis tissue. Because cellular models have demonstrated a role for AC in immune processes and cancer (28)(29)(30)(31)(32)(33), we generated a myeloidspecific KO model of AC to investigate the role of the enzyme in intestinal inflammation using the model of dextran sulfate sodium (DSS)-induced colitis. In this study, we demonstrate a novel role for AC in the myeloid compartment that regulates the threshold of neutrophil recruitment and the production of inflammatory cytokines in the colon.…”