Fig 1: Hypothetical model of NLRP3 inflammasome activation and S1P signalling dysregulation in mucus-obstructed bronchioles. Unobstructed bronchioles (AIR): NLRP3 is mostly in monomeric state, only background levels of cleaved IL-1ß are detected; SPHK1 generates cytosolic S1P, part of which is exported via SPNS2 for extracellular (inside-out) signalling via S1PRs; SPHK2 generates S1P mostly for intracellular signalling. Obstructed bronchioles (MUCUS): Increased oligomerization of NLRP3 (inflammasome activation) in either epithelium or infiltrating leucocytes results in IL-1ß cleavage and increased luminal specks of NLRP3/IL-1ß; decrease of SPNS2 and SPHK2 results in reduction of extra- and intracellular S1P signalling