The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

Background: inflammasome-activated il-1β plays a major role in lung neutrophilic inflammation induced by inhaled silica. however,the exact mechanisms that contribute to the initial production of precursor il-1β (pro-il-1β) are still unclear. here,we assessed the implication of alarmins (il-1α,il-33 and hmgb1) in the lung response to silica particles and found that il-1α is a master cytokine that regulates il-1β expression. methods: pro- and mature il-1β as well as alarmins were assessed by elisa,western blot or qrt-pcr in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts,cxcr2 expression and degree of histological injury. results: we found that the early release of il-1α and il-33,but not hmgb1 in alveolar space preceded the lung expression of pro-il-1β and neutrophilic inflammation in silica-treated mice. in vitro,the production of pro-il-1β by alveolar macrophages was significantly induced by recombinant il-1α but not by il-33. neutralization or deletion of il-1α reduced il-1β production and neutrophil accumulation after silica in mice. finally,il-1α released by j774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles. conclusions: we demonstrated that in response to silica exposure,il-1α is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of il-1β production. moreover,we demonstrated that in vitro il-1α release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles. © rabolli et al.; licensee biomed central.