Hypothesis regarding the role of IL-1β processing in the inflammatory response following mechanical ventilation. We present the following hypothesis based on our results and previous findings. Mechanical ventilation causes mechanotransduction and cell and/or tissue damage. This causes the release of danger-associated molecular patterns (DAMPs) that activate TLR4 and possibly other pattern recognition receptors. Ligation of these receptors induces production of cytokines, most importantly IL-1β. Subsequently, KC is produced, leading to neutrophil recruitment to the lungs. Pro-IL-1β processing to bioactive IL-1β could occur intracellularly by caspase-1, although in our model, it only plays a minor role in IL-1β bioactivation, not excluding that it may be involved at the onset of the inflammatory process, when very few neutrophils are present. The majority of pro-IL-1β is excreted in the inactive form and then cleaved by factors released by neutrophils, such as neutrophil serine proteases. Finally, active IL-1β present extracellularly binds to the IL-1R, which in turn leads to the production of more cytokines and hence positive amplification of the inflammatory response. As such, a positive feedback loop is activated which could be an explanation for the extensive inflammatory response observed following mechanical ventilation. Numbers 1 to 4 represent the experiments performed in this study and correspond to the figure numbers in this paper. References  and  refer to previous studies performed by our group.