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Predictable irreversible switching between acute and chronic inflammation

Abudukelimu, A., Barberis, Matteo, Redegeld, F.A., Sahin, N. and Westerhoff, H.V. (2018) Predictable irreversible switching between acute and chronic inflammation Frontiers in Immunology, 9, 1596. pp. 1-16.

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Many a disease associates with inflammation. Upon binding of antigen-antibody complexes to immunoglobulin-like receptors, mast cells release tumor necrosis factor-α and proteases, causing fibroblasts to release endogenous antigens that may be cross reactive with exogenous antigens. We made a predictive dynamic map of the corresponding extracellular network. In silico, this map cleared bacterial infections, via acute inflammation, but could also cause chronic inflammation. In the calculations, limited inflammation flipped to strong inflammation when cross-reacting antigen exceeded an "On threshold." Subsequent reduction of the antigen load to below this "On threshold" did not remove the strong inflammation phenotype unless the antigen load dropped below a much lower and subtler "Off" threshold. In between both thresholds, the network appeared caught either in a "low" or a "high" inflammatory state. This was not simply a matter of bi-stability, however, the transition to the "high" state was temporarily revertible but ultimately irreversible: removing antigen after high exposure reduced the inflammatory phenotype back to "low" levels but if then the antigen dosage was increased only a little, the high inflammation state was already re-attained. This property may explain why the high inflammation state is indeed "chronic," whereas only the naive low-inflammation state is "acute." The model demonstrates that therapies of chronic inflammation such as with anti-IgLC should require fibroblast implantation (or corresponding stem cell activation) for permanence in order to redress the irreversible transition. © 2018 Abudukelimu, Barberis, Redegeld, Sahin and Westerhoff.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Abudukelimu, A.
Redegeld, F.A.
Sahin, N.
Westerhoff, H.V.
Date : 7 August 2018
Funders : Biotechnology and Biological Sciences Research Council (BBSRC)
DOI : 10.3389/fimmu.2018.01596
Copyright Disclaimer : © 2018 Abudukelimu, Barberis, Redegeld, Sahin 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; Cross-reacting antigen; Inflammation; Innate immunity; Irreversible transition; Modelling
Depositing User : Clive Harris
Date Deposited : 10 Apr 2019 07:46
Last Modified : 10 Apr 2019 07:46

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