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

Background: Inflammasome-activated IL-1 beta 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-1 beta (pro-IL-1 beta) are still unclear. Here, we assessed the implication of alarmins (IL-1 alpha, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1 alpha is a master cytokine that regulates IL-1 beta expression. Methods: Pro-and mature IL-1 beta 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-1 alpha and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1 beta and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1 beta by alveolar macrophages was significantly induced by recombinant IL-1 alpha but not by IL-33. Neutralization or deletion of IL-1 alpha reduced IL-1 beta production and neutrophil accumulation after silica in mice. Finally, IL-1 alpha 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-1 alpha is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1 beta production. Moreover, we demonstrated that in vitro IL-1 alpha release from macrophages can be used to predict the acute inflammogenic activity of silica micro-and nanoparticles.