Resolved vs. uncontrolled inflammation: a mathematical model to decipher the role of innate immunity

Abstract

ABSTRACTNeutrophils and macrophages related processes have been described as relevant during the inflammation resolution after an acute damage. Nevertheless, understanding the impact of both cells and the processes in which they are involved is still an open debate. Specifically, several studies have been focused on elucidate their impact in the dynamic outcome of resolution vs uncontrolled response. In this work, we develop a mathematical model that describe the dynamic of the innate immune response after an acute damage. Our model includes all the described processes that mediate this response, including the regulatory mechanisms carried out by type-2 macrophages (M2). Additionally, we estimate the resolution indices to quantify the efficiency of resolution mechanisms by controlling the initial expansion of Neutrophils and/or the subsequent contraction kinetics of the cell response. We predict that the processes of cells influx into the inflamed site, Neutrophil apoptosis and type-1 macrophage (M1)-mediated efferocytosis, are the ones that have an impact on the final outcome, but interfering in different resolution indices. In particular, we predict that the partial reduction of Neutrophil influx and the increase of M1-mediated efferocytosis rate are the best strategies to control the Neutrophil initial expansion. On the other hand, the partial reduction of M1 cells influx or the increase of Neutrophil apoptosis rate are predicted as good strategies to accelerate the Neutrophils decay during the contraction phase of the response.