In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.

The 6-kDa early secretory antigenic target (ESAT-6) of Mycobacterium tuberculosis is strongly correlated with subversion of innate immune responses against invading mycobacteria. To understand the role of ESAT-6 in macrophage response against M. tuberculosis, the effects of ESAT-6 on macrophage generation of reactive oxygen species (ROS) and production of cytokines were studied. ESAT-6-induced macrophage secretion of monocyte chemoattractant protein-1 and TNF-α was found in a time- and dose-dependent manner. Signaling inhibition experiments indicate that NF-κB activation mediated by p38/JNK mitogen-activated protein kinase (MAPK) was involved in ESAT-6-triggered cytokine production. Moreover, TLR2 was engaged in ESAT-6-stimulated macrophage activation via rapidly induced ROS production and regulated activation of JNK/p38 MAPKs and NF-κB. More importantly, NADPH oxidase-mediated ROS generation is required during this process. Our study has identified a novel signal transduction pathway involving NADPH-ROS-JNK/p38-NF-κB in ESAT-6-induced cytokine production from macrophages. These findings provide an important evidence to understand the pathogenesis of M. tuberculosis infection in the modulation of the immune response.

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