A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis

Journal of Pharmacokinetics and Pharmacodynamics, vol. 49, pp. 645–655

Abstract

Sepsis is a life-threatening condition driven by the dysregulation of the host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed to obtain a deeper mechanistic insight into sepsis pathogenesis and to evaluate promising novel therapeutic targets, with a focus on Toll-like receptor 4 (TLR4)-mediated pathways. A Boolean network of regulatory relationships was developed for key immune components associated with sepsis pathogenesis after TLR4 activation. Perturbation analyses were conducted to identify therapeutic targets associated with organ dysfunction or antibacterial activity. The developed model consisted of 42 nodes and 183 interactions. Perturbation analyses suggest that over-expression of tumour necrosis factor alpha (TNF-α) or inhibition of soluble receptor sTNF-R, tissue factor, and inflammatory cytokines (IFN-γ, IL-12) may lead to a reduced activation of organ dysfunction related endpoints. Over-expression of complement factor C3b and C5b led to an increase in the bacterial clearance related endpoint. We identified that combinatory blockade of IFN-γ and IL-10 may reduce the risk of organ dysfunction. Finally, we found that combining antibiotic treatment with IL-1β targeted therapy may have the potential to decrease thrombosis. In summary, we demonstrate how existing biological knowledge can be effectively integrated using Boolean network analysis for hypothesis generation of potential treatment strategies and characterization of biomarker responses associated with the early inflammatory response in sepsis.

Authors 9

1. Feiyan Liu Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

2. Linda B. S. Aulin Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

3. Sebastiaan S. A. Kossen Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

4. Julius Cathalina Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

5. Marlotte Bremmer Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

6. Amanda C. Foks Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

7. Piet H. van der Graaf Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Certara QSP, Canterbury Innovation Centre, Canterbury, UK

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

8. Matthijs Moerland Aachen Centre for Human Drug Research (CHDR)

   Leiden University Medical Center · Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, Netherlands

   Leiden University Medical Center, Leiden, The Netherlands

9. J. G. Coen van Hasselt corresponding Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. coen.vanhasselt@lacdr.leidenuniv.nl

   Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands