Loss of acid ceramidase activity in a murine model of Farber disease leads to an early and profound immuno-phenotype that reflects alterations in both the innate and adaptive immune cell populations

Abstract

Farber disease is an ultra-rare lysosomal storage disorder where a deficiency of acid ceramidase activity leads to the accumulation of ceramide and the formation of granulomas which, in conjunction with a chronic inflammatory state, likely results in tissue damage. A rapidly progressive murine knock-in Asah1P361R/P361R model of Farber disease recapitulates many aspects of the human disease, including an increase in ceramide and pronounced tissue inflammation. The focus of this study was to describe the aberrant immune cells in this disease model. Blood, livers, lungs, and spleens were collected from 4- to 8-week old litter-matched Farber and wild-type mice for characterization by flow cytometry. Characterization of the monocyte population revealed a marked increase in the frequency of MHCII−CD11bhiLy6C+ cells (3–6 fold vs WT). These cells were highly activated as evidenced by CD86 expression, and skewed toward a pro-inflammatory M1 phenotype, based on CD38 expression. A concurrent decrease in CD206+ anti-inflammatory M2 macrophages was identified. In addition to the macrophage compartment, a profound increase in neutrophils in the spleen, liver, and lung was evident by 4 weeks of age (2–7 fold vs. wild-type). Marked differences in the adaptive immune compartment also were noted, with a clear increase in the frequency of plasmablasts (precursors to immunoglobulin-producing plasma cells), likely secondary to the increase in pro-inflammatory monocytes. Importantly, the alterations observed in the tissues were reflected in the blood of Farber mice. In summary, these data expand the characterization of the murine Farber disease model and provide insight into the immuno-phenotype of Farber disease.