Silicosis is considered an irreversible chronic inflammatory disease caused by the inhalation of crystalline
silica (cSiO2). The cycle of
inflammation that drives
silicosis and other particle-caused
respiratory diseases is mediated by NLRP3
inflammasome activity in macrophages resulting in the release of IL-1β. Lysosomal membrane permeability (LMP) initiated by inhaled particles is the key regulatory step in leading to NLRP3 activity. In addition to its role in LMP, the lysosome is crucial to cellular
cholesterol trafficking. Lysosomal
cholesterol has been demonstrated to regulate LMP while cationic amphiphilic drugs (CADs) reduce
cholesterol trafficking from lysosomes and promote endolysosomal
cholesterol accumulation as seen in
Niemann Pick disease. Using a bone marrow derived macrophage (BMdM) model, four CADs were examined for their potential to reduce cSiO2-induced
inflammation. Here we found that FDA-approved CAD drugs
imipramine,
hydroxychloroquine,
fluvoxamine, and
fluoxetine contributed to reduced LMP and IL-1β release in cSiO2 treated BMdM. These drugs inhibited lysosomal enzymatic activity of
acid sphingomyelinase, decreased lysosomal proteolytic function, and increased lysosomal pH. CADs also demonstrated a significant increase in lysosomal-associated free
cholesterol. Increased lysosomal
cholesterol was associated with a significant reduction in cSiO2 induced LMP and IL-1β release. In contrast, reduced lysosomal
cholesterol significantly exacerbated cSiO2-induced IL-1β release and reduced the protective effect of CADs on IL-1β release following cSiO2 exposure. Taken together, these results suggest that CAD modification of lysosomal
cholesterol may be used to reduce LMP and cSiO2-induced
inflammation and could prove an effective therapeutic for
silicosis and other particle-caused
respiratory diseases.