Role of NLRP3 inflammasome and ATP in S100A12-induced MUC5AC production in airway epithelial cells

Abstract

Increasing evidence shows that danger-associated molecular patterns (DAMPs) play a proinflammatory role in the pathogenesis of airway obstructive diseases such as severe asthma and chronic obstructive pulmonary disease. S100 proteins and ATP are newly identified DAMPs in inflamed airways. NLRP3 serves as a pivotal player in innate immune system and has been linked to inflammatory airway diseases. We have previously demonstrated that S100 proteins induce production of MUC5AC, a major mucin in the conducting airway mucosa. The purpose of this study was to determine the involvement of NLRP3 inflammasome in and the contribution of ATP to S100 protein-induced MUC5AC production by NCI-H292 airway epithelial cells. Stimulation with either S100A12 or ATP alone led to MUC5AC production at comparable levels, accompanied by increases in NF-kB activation, NLRP3 synthesis, active caspase-1, and IL-1b secretion. Simultaneous treatment with both stimuli led to increased MUC5AC production in an additive manner, with a more marked increase in co-localization of NLRP3 and caspase-1 than either treatment alone. Blocking of NLRP3 synthesis and NLRP3 inflammasome activation resulted in abrogation of ATP- and S100A12-mediated IL-1b secretion and MUC5AC production. Thus, these two danger signals independently contribute to MUC5AC production in airway epithelial cells through NLRP3 inflammasome activation.