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Front. Immunol. | doi: 10.3389/fimmu.2018.00637

Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling.

Daniel Moyo1, 2,  Lynette Beattie1, Paul Andrews2, 3, John Moore1,  Jonathan Timmis2, 3, Amy Sawtell1, Stefan Hoehme4, Adam Sampson5 and  Paul Kaye1*
  • 1Hull York Medical School and Deptartment of Biology, University of York, United Kingdom
  • 2Department of Electronics, University of York, United Kingdom
  • 3SimOmics Ltd, United Kingdom
  • 4Institute for Computer Science, Leipzig University, Germany
  • 5Department of Computer Science, Abertay University, United Kingdom

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation.

Keywords: Kupffer Cells, granulomas, Inflammation, Leishmania, NKT cells, Agent-based modeling, computational immunology, Liver

Received: 07 Jan 2018; Accepted: 14 Mar 2018.

Edited by:

Takayuki Yoshimoto, Tokyo Medical University, Japan

Reviewed by:

Francesco Pappalardo, Università degli Studi di Catania, Italy
Shinichi Hashimoto, Kanazawa University, Japan  

Copyright: © 2018 Moyo, Beattie, Andrews, Moore, Timmis, Sawtell, Hoehme, Sampson and Kaye. 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 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.

* Correspondence: Prof. Paul Kaye, University of York, Hull York Medical School and Deptartment of Biology, University of York, Wentworth Way, York, YO10 5DD, N. Yorks, United Kingdom,