Fabry disease peripheral blood immune cells release inflammatory cytokines: Role of globotriaosylceramide

DE FRANCESCO PN,; MUCCI JM; CECI R; FOSSATI CA; ROZ

MOLECULAR GENETICS AND METABOLISM

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2013 vol. 109 p. 93 - 99

1096-7192

Fabry disease is an X-linked lysosomal disorder (LD) due to deficiency of the enzyme α-galactosidase A(αGal), which leads to the accumulation of neutral glycosphingolipids, mainly globotriaosylceramide(Gb3). Several mechanisms contribute to the diverse physiopathological alterations observed in this disease,and it has been suggested that an underlying proinflammatory state could play a significant role. The aim ofthis study is to investigate the presence of a proinflammatory state in the different subsets of peripheralblood mononuclear cells (PBMC) and to understand the mechanisms that contribute to its onset and perpetuation.We have shown that cultured PBMC from Fabry patients present a higher proinflammatory cytokineexpression and production. Moreover, we determined that among PBMC, dendritic cells and monocytespresent a basal proinflammatory cytokine production profile, which is further exacerbated with an inflammatorystimulus. Finally we established that normal, monocyte-derived dendritic cells and macrophages displaythe same proinflammatory profile when cultured in the presence of Gb3 and an inhibitor of αGal. Furthermore,this effect can be abolished using a TLR4 blocking antibody, indicating that TLR4 is necessary in the process.In summary, our results demonstrate the presence of a proinflammatory state involving two key subsetsof innate immunity, and provide direct evidence of Gb3 having a proinflammatory role, likely mediated byTLR4, a finding that could help in the understanding of the underlying causes of the inflammatory pathogenesisof Fabry disease.