Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation.Author Summary: A recent approach to quantitatively characterize the timing and intensity of the inflammatory response relies on the use of four quantities termed inflammation indices. The values of the inflammation indices may reflect the differences between normal and pathological inflammation, and may be used to gauge the effects of therapeutic interventions aimed to control inflammation. Yet, the specific inflammatory mechanisms that can be targeted to selectively control these indices remain unknown. Here, we developed and applied a computational strategy to identify potential target mechanisms to regulate such indices. We used our recently developed model of local inflammation to simulate thousands of inflammatory scenarios. We then subjected the corresponding inflammation index values to sensitivity and correlation analysis. We found that the inflammation indices may be significantly influenced by the macrophage influx and efflux rates, as well as by the degradation rates of three specific molecular mediators. These results suggested that the indices can be effectively regulated by individual or combined inhibition of those molecular mediators, which we confirmed by computational experiments. Taken together, our results highlight possible targets of therapeutic intervention that can be used to control both the timing and the intensity of the inflammatory response.