Macrophage Transactivation for Chemokine Production Identified as a Negative Regulator of Granulomatous Inflammation Using Agent-Based Modeling

• Published in: Frontiers in immunology Vol. 9; p. 637
• Main Authors: Moyo, Daniel, Beattie, Lynette, Andrews, Paul S, Moore, John W J, Timmis, Jon, Sawtell, Amy, Hoehme, Stefan, Sampson, Adam T, Kaye, Paul M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 27.03.2018
• Subjects: agent-based modeling; Animals; Cells, Cultured; Chemokines - genetics; Disease Models, Animal; Gene Expression Profiling; Granuloma - immunology; granulomas; Humans; Immunology; inflammation; Inflammation - immunology; kupffer cells; Kupffer Cells - physiology; Leishmania; Leishmania donovani - physiology; Leishmaniasis, Visceral - immunology; Liver - immunology; Liver - parasitology; Macrophages - physiology; Mice; Mice, Inbred C57BL; natural killer T cells; Natural Killer T-Cells - immunology; Systems Analysis; Transcriptional Activation; kupffer cells; computational immunology; inflammation; liver; Leishmania; agent-based modeling; granulomas; natural killer T cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.00637

Cellular activation 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 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 -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.