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

PLoS Comput Biol. 2015 Dec 3;11(12):e1004460. doi: 10.1371/journal.pcbi.1004460. eCollection 2015 Dec.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Computer Simulation
  • Humans
  • Immunity, Innate / immunology*
  • Inflammation / immunology*
  • Inflammation / pathology
  • Interleukin-8 / immunology*
  • Macrophage Activation / immunology
  • Macrophages / immunology
  • Models, Immunological*
  • Severity of Illness Index
  • Transforming Growth Factor beta / immunology*
  • Tumor Necrosis Factor-alpha / immunology*


  • Interleukin-8
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha

Grant support

The authors were supported by the Clinical and Rehabilitative Medicine Research Program of the U.S. Army Medical Research and Materiel Command, Fort Detrick, MD ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.