Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
Department of Computer Science, University of York, York, United Kingdom.
Front Immunol. 2018 Mar 27;9:637. doi: 10.3389/fimmu.2018.00637. eCollection 2018.
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.
干扰素、细胞因子和趋化因子激活细胞是放大免疫效应功能和限制病原体传播的一种常见机制。然而，最佳的宿主反应还需要限制与炎症相关的附带损害。在肉芽肿炎症的情况下，情况尤其如此，过多的和/或过于华丽的肉芽肿可能会产生重大的病理后果。在这里，我们结合了转录组学、基于代理的建模和实验方法来研究实验性利什曼病小鼠模型中肝肉芽肿形成的限制因素。我们证明，感染肝脏中未感染的枯否细胞产生趋化因子可促进与感染的 KC 竞争可用的 iNKT 细胞，最终抑制肉芽肿炎症的程度。我们提出趋化因子产生的转激活作为一种新的广泛适用的机制，可能在感染早期发挥作用，以限制过度的局灶性炎症。
