Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice.

Hunter syndrome or mucopolysaccharidosis type II (MPS II) is an X-linked recessive disease caused by the deficiency of iduronate 2-sulfatase (IDS), leading to storage of undegraded heparan and dermatan sulfate. Patients with the severe form present neurological abnormalities, but the mechanisms of such alterations are unknown. Here, we hypothesized that the undegraded substances found in this disease could be recognized as damage-associated molecular patterns (DAMPS), leading to activation of the inflammasome. Brains from 2 and 5 months normal and MPS II mice were studied. We observed an increase in cathepsin B activity in the brain tissue and leakage of this enzyme from the lysosome to the cytoplasm in a MPS II neuronal cell line, which is a known activator of the inflammasome. Furthermore, Caspase-1 activity and IL-1-beta levels were elevated at 5 months, confirming that this pathway is indeed altered. Our results suggest that undegraded GAG activate the inflammasome pathway in MPS II and future studies could focus on blocking such pathway to better understand the role of this process to the pathogenesis of MPS II.