IDEHU   05542
INSTITUTO DE ESTUDIOS DE LA INMUNIDAD HUMORAL PROF. RICARDO A. MARGNI
Unidad Ejecutora - UE
artículos
Título:
Fabry disease peripheral blood immune cells release inflammatory cytokines: role of globotriaosylceramide
Autor/es:
DE FRANCESCO P N; MUCCI J M; CECI R; FOSSATI C A; ROZENFELD P A
Revista:
MOLECULAR GENETICS AND METABOLISM
Editorial:
ACADEMIC PRESS INC ELSEVIER SCIENCE
Referencias:
Lugar: Amsterdam; Año: 2013 vol. 109 p. 93 - 99
ISSN:
1096-7192
Resumen:
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
of this study is to investigate the presence of a proinflammatory state
in the different subsets of peripheral blood 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 cytokine expression and production.
Moreover, we determined that among PBMC, dendritic cells and monocytes
present a basal proinflammatory cytokine production profile, which is
further exacerbated with an inflammatory stimulus. Finally we
established that normal, monocyte-derived dendritic cells and
macrophages display the 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 subsets of innate
immunity, and provide direct evidence of Gb3 having a proinflammatory
role, likely mediated by TLR4, a finding that could help in the
understanding of the underlying causes of the inflammatory pathogenesis
of Fabry disease.