Abstract
In an inflammatory setting, macrophages can be polarized to an inflammatory M1 phenotype or to an anti-inflammatory M2 phenotype, as well as existing on a spectrum between these two extremes. Dysfunction of this phenotypic switch can result in a population imbalance that leads to chronic wounds or disease due to unresolved inflammation. Therapeutic interventions that target macrophages have therefore been proposed and implemented in diseases that feature chronic inflammation such as diabetes mellitus and atherosclerosis. We have developed a model for the sequential influx of immune cells in the peritoneal cavity in response to a bacterial stimulus that includes macrophage polarization, with the simplifying assumption that macrophages can be classified as M1 or M2. With this model, we were able to reproduce the expected timing of sequential influx of immune cells and mediators in a general inflammatory setting. We then fit this model to in vivo experimental data obtained from a mouse peritonitis model of inflammation, which is widely used to evaluate endogenous processes in response to an inflammatory stimulus. Model robustness is explored with local structural and practical identifiability of the proposed model a posteriori. Additionally, we perform sensitivity analysis that identifies the population of apoptotic neutrophils as a key driver of the inflammatory process. Finally, we simulate a selection of proposed therapies including points of intervention in the case of delayed neutrophil apoptosis, which our model predicts will result in a sustained inflammatory response. Our model can therefore provide hypothesis testing for therapeutic interventions that target macrophage phenotype and predict outcomes to be validated by subsequent experimentation.
Highlights
Macrophages play an essential role in both the progression and the resolution of inflammation
Using experimental data and mathematical analysis, we develop a model for the inflammatory response that includes macrophage polarization between M1 and M2 phenotypes
The modulation of macrophage population has been suggested as a strategy to dampen inflammation in diseases that feature chronic inflammation, such as diabetes and atherosclerosis
Summary
Macrophages play an essential role in both the progression and the resolution of inflammation These contradictory roles may be explained by the idea of a spectrum of macrophage phenotypes, ranging from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype at either extreme, with diverse subpopulations of macrophages in between [1,2,3,4]. Another possible explanation is that macrophages exhibit typically M1 or M2 type functions to varying degrees at various points in time, or there are portions of each type present at each of the different phases of inflammation [5]. There is an increased association of M2 polarized macrophages with solid tumor formation [8, 9]
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