title: Signal transduction analysis of the NLRP3-inflammasome pathway after cellular damage and its paracrine regulation.
abstract: Activation of the NLRP3-inflammasome pathway and production of the inflammatory cytokine IL-1B after cellular damage caused by infarct or infection is a key process in several diseases such as acute myocardial infarction and inflammatory bowel disease. However, while the molecular triggers of the NLRP3-pathway after cellular damage are well known, the mechanisms that sustain or confine its activity are currently under investigation. We present here an Ordinary Differential Equation-based model that investigates the mechanisms of inflammasome activation and regulation in monocytes to predict IL-1β activation kinetics upon a two-step activation by Damage-Associate-Molecular-Particles (DAMP) and extracellular ATP. Assuming both activation signals to be concomitantly present or present with a delay of 12h, the model predicted a transient IL-1β activation at different concentration levels dependent on signal synchronisation. Introducing a positive feedback loop mediated by active IL-1β resulted in a sustained IL-1β activation, hence arguing for a paracrine signalling between inflammatory cells to guarantee a temporally stable inflammatory response. We then investigate mechanisms that control termination of inflammation using two recently identified molecular intervention points in the inflammasome pathway. We found that a more upstream regulation, by attenuating production of the IL-1β-proform, was more potent in attenuating active IL-1β production than direct inhibition of the NLRP3-inflammasome. Interestingly, ablating this upstream negative feedback led to a high variability of IL-1β production in monocytes from different subjects, consistent with a recent pre-clinical study. We finally discuss the relevance and implications of our findings in disease models of acute myocardial infarction and spontaneous colitis.
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Denise
authors.initials: D
authors.lastname: Veltman
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Thessa
authors.initials: T
authors.lastname: Laeremans
authors.affiliation: School of Pharmacy and Biomedical Sciences, Univ. of Central Lancashire, Preston, UK.
authors.forename: Egle
authors.initials: E
authors.lastname: Passante
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium; Institute for Automation Engineering (IFAT), Laboratory for Systems Theory and Automatic Control, Otto-von-Guericke University Magdeburg, 39106 Magdeburg - Germany. Electronic address: heinrich.huber@ovgu.de.
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Huber
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002477:Cells / Q000473:pathology; D002478:Cells, Cultured; D005246:Feedback; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D008962:Models, Theoretical; D009000:Monocytes / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000255:Adenosine Triphosphate
keywords: Inflammatory diseases; Interferons; NLRP3-Inflammasome; Ordinary Differential Equations; Signal transduction modelling