Spatiotemporal programming of a simple inflammatory process

Abstract

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.