Kepler Thomas B, Chan Cliburn
Department of Biostatistics and Bioinformatics, Center for Computational Immunology, Duke University, Durham, NC 27705, USA.
Immunol Rev. 2007 Apr;216:153-63. doi: 10.1111/j.1600-065X.2007.00500.x.
Inflammatory processes are essential for recruiting leukocytes to the site of infection in sufficient numbers and for initiating adaptive immunity. Unresolved inflammation, however, can cause serious damage to host tissues and indeed is known to contribute to the pathology of many acute and chronic diseases. Leukocytes activated by pathogen-associated molecular patterns (PAMPs) respond, in part, by secreting tumor necrosis factor (TNF) and by shedding the TNF receptor, the latter process occurring with slower kinetics. We suggest that this pro/anti-inflammatory switch is a simple program that helps ensure the resolution of inflammation. To examine this idea, we have developed a microsimulation model in which individual leukocytes with non-trivial internal dynamics move in three-dimensional tissues and interact with each other and with stromal cells through diffusing soluble factors, including TNF, the soluble form of the tumor necrosis factor receptor (sTNFR), and the chemokine monocyte chemotactic protein-1. By manipulating parameters in numerical experiments with soluble PAMP stimulation of varying intensity and duration, we elicit qualitatively distinct patterns of innate immune response and elucidate a key relationship between leukocyte density enhancement by chemotaxis and paracrine TNF signaling. By reducing the rate of sTNFR shedding, we induce massive unresolved inflammation, underscoring a potentially crucial role of sTNFR in controlling innate immunity.
炎症过程对于将白细胞大量募集到感染部位以及启动适应性免疫至关重要。然而，未消退的炎症会对宿主组织造成严重损害，并且已知会导致许多急性和慢性疾病的病理变化。由病原体相关分子模式（PAMP）激活的白细胞部分通过分泌肿瘤坏死因子（TNF）以及通过脱落TNF受体做出反应，后一过程以较慢的动力学发生。我们认为这种促炎/抗炎转换是一个简单的程序，有助于确保炎症的消退。为了检验这一观点，我们开发了一个微观模拟模型，其中具有复杂内部动力学的单个白细胞在三维组织中移动，并通过扩散可溶性因子（包括TNF、肿瘤坏死因子受体的可溶性形式（sTNFR）和趋化因子单核细胞趋化蛋白-1）相互作用以及与基质细胞相互作用。通过在数值实验中操纵不同强度和持续时间的可溶性PAMP刺激的参数，我们引发了定性上不同的先天免疫反应模式，并阐明了趋化作用增强白细胞密度与旁分泌TNF信号传导之间的关键关系。通过降低sTNFR脱落的速率，我们诱导了大量未消退的炎症，强调了sTNFR在控制先天免疫中的潜在关键作用。
