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

Virginie Rabolli, Anissa Alami Badissi, Raynal Devosse, Francine Uwambayinema, Yousof Yakoub, Mihaly Palmai-Pallag, Astrid Lebrun, Valentin De Gussem, Isabelle Couillin, Bernard Ryffel, Etienne Marbaix, Dominique Lison, François Huaux

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