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Complex Stability and an Irrevertible Transition Reverted by Peptide and Fibroblasts in a Dynamic Model of Innate Immunity

Abudukelimu, Abulikemu, Barberis, Matteo, Redegeld, Frank, Sahin, Nilgun, Sharma, Raju P. and Westerhoff, Hans V. (2020) Complex Stability and an Irrevertible Transition Reverted by Peptide and Fibroblasts in a Dynamic Model of Innate Immunity Frontiers in Immunology, 10, 3091.

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We here apply a control analysis and various types of stability analysis to an in silico model of innate immunity that addresses the management of inflammation by a therapeutic peptide. Motivation is the observation, both in silico and in experiments, that this therapy is not robust. Our modeling results demonstrate how (1) the biological phenomena of acute and chronic modes of inflammation may reflect an inherently complex bistability with an irrevertible flip between the two modes, (2) the chronic mode of the model has stable, sometimes unique, steady states, while its acute-mode steady states are stable but not unique, (3) as witnessed by TNF levels, acute inflammation is controlled by multiple processes, whereas its chronic-mode inflammation is only controlled by TNF synthesis and washout, (4) only when the antigen load is close to the acute mode's flipping point, many processes impact very strongly on cells and cytokines, (5) there is no antigen exposure level below which reduction of the antigen load alone initiates a flip back to the acute mode, and (6) adding healthy fibroblasts makes the transition from acute to chronic inflammation revertible, although (7) there is a window of antigen load where such a therapy cannot be effective. This suggests that triple therapies may be essential to overcome chronic inflammation. These may comprise (1) anti-immunoglobulin light chain peptides, (2) a temporarily reduced antigen load, and (3a) fibroblast repopulation or (3b) stem cell strategies.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Abudukelimu, Abulikemu
Redegeld, Frank
Sahin, Nilgun
Sharma, Raju P.
Westerhoff, Hans V.
Date : 14 February 2020
Funders : University of Amsterdam - Priority Area Systems Biology, University of Amsterdam - Swammerdam Institute for Life Science Starting Grant, EU-H2020
DOI : 10.3389/fimmu.2019.03091
Grant Title : Marie Skłodowska-Curie Innovative Training Networks
Copyright Disclaimer : Copyright © 2020 Abudukelimu, Barberis, Redegeld, Sahin, Sharma and Westerhoff. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords : bi-stability; fibroblasts; inflammation; innate immunity; irreversible transitions; systems biology.
Depositing User : James Marshall
Date Deposited : 18 Jun 2020 09:32
Last Modified : 18 Jun 2020 09:32

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