Macrophage Transactivation for chemokine Production identified as a negative regulator of granulomatous inflammation Using agent-Based Modeling
Authored by Stefan Hoehme, Jon Timmis, Daniel Moyo, Lynette Beattie, Paul S Andrews, John W J Moore, Amy Sawtell, Adam T Sampson, Paul M Kaye
Date Published: 2018
DOI: 10.3389/fimmu.2018.00637
Sponsors:
Wellcome Trust
United Kingdom Engineering and Physical Sciences Research Council (EPSRC)
British Medical Research Council
Platforms:
No platforms listed
Model Documentation:
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Abstract
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.
Tags
Agent-based modeling
inflammation
computational immunology
Gene-expression
T-cells
Liver
Kupffer cells
Rat-liver
Granulomas
Leishmania
Natural killer t
cells
Leishmania-donovani infection
Invariant nkt cells
Posttranscriptional regulation
Mycobacterial
granulomas
Visceral leishmaniasis
Lymphoid-cells