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

Daniel Moyo, Lynette Beattie, Paul S. Andrews, John W.J. Moore, Jon Timmis, Amy Sawtell, Stefan Hoehme, Adam T. Sampson, Paul M. Kaye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (SciVal)

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.

Original languageEnglish
Article number637
JournalFrontiers in Immunology
Volume9
Issue numberMAR
DOIs
Publication statusPublished - 27 Mar 2018

Keywords

  • Agent-based modeling
  • Computational immunology
  • Granulomas
  • Inflammation
  • Kupffer cells
  • Leishmania
  • Liver
  • Natural killer T cells
  • Humans
  • Transcriptional Activation
  • Gene Expression Profiling
  • Leishmania donovani/physiology
  • Inflammation/immunology
  • Systems Analysis
  • Chemokines/genetics
  • Disease Models, Animal
  • Kupffer Cells/physiology
  • Mice, Inbred C57BL
  • Cells, Cultured
  • Natural Killer T-Cells/immunology
  • Leishmaniasis, Visceral/immunology
  • Animals
  • Liver/immunology
  • Mice
  • Granuloma/immunology
  • Macrophages/physiology

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