Signal transduction analysis of the NLRP3-inflammasome pathway after cellular damage and its paracrine regulation. (21st February 2017)

• Record Type: Journal Article
• Authors: Veltman, Denise; Laeremans, Thessa; Passante, Egle; Huber, Heinrich J.
• Is Part Of: Journal of theoretical biology. Volume 415(2017)
• Page Start: 125
• Page End: 136
• Publication Date: 2017-02-21
• Subjects: Signal transduction modelling -- NLRP3-Inflammasome -- Interferons -- Inflammatory diseases -- Ordinary Differential Equations; Biology -- Periodicals; Biological Science Disciplines -- Periodicals; Biology -- Periodicals; Biologie -- Périodiques; Theoretische biologie; Biology; Periodicals; 571.05
• DOI: 10.1016/j.jtbi.2016.12.016
• Languages: English
• ISSNs: 0022-5193

Abstract

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 12 h, 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. Highlights: We provide a pathway model of the NLRP3-inflammasome after cellular damage. NLRP3-inflammasome attenuation by paracrine IFN-I is more potent than by IFN-II. Change from IFN-II to IFN-I may stop inflammation during tissue repair after infarct. Impairment of IFN-I feedback can lead to hyperinflammation as in spontaneous colitis. Regulation of inflammation may directly be encoded within regulatory pathways.