Macrophage polarization as a potential therapeutic target for atherosclerosis: a dynamic stochastic modelling study

Abstract

We proposed a dynamic stochastic mathematical model to evaluate the role of macrophage polarization in plaque development. The dynamic process of macrophages from proliferation to death was simulated under different lipid microenvironments. The probability of macrophage phenotypic switching was described using a Bernoulli distribution where the stochastic variable was determined by the local lipid level. Moreover, the interactions between macrophages and microenvironmental factors vary with macrophage phenotype. We investigated the distribution of key microenvironmental factors, the dynamics of macrophage polarization and its influence on foam cell formation. M1 macrophages were found to predominate in advanced plaque corresponding to the exacerbated inflammation observed in mice experiments. The imbalance between the deposition of oxidized low-density lipoprotein and phagocytic effects of macrophages governed the formation of foam cells. Furthermore, we simulated targeted therapies by either directly inhibiting the polarization probability to M1 macrophages or indirectly regulating macrophage polarization due to high-density lipoprotein levels. Comparison of simulation results with experimental findings in both therapies indicated that the intervention and regulation of macrophage polarization could influence plaque microenvironment and subsequently induce plaque regression, especially in the early stage. The proposed modelling system can facilitate the evaluation of novel therapies targeting macrophage polarization.

Keywords: macrophages; polarization; target therapy.

Figure 1.

Schematic diagram of the model simulation area.

Figure 2.

Schematic diagram of the interactions of the main factors in the model.

Figure 3.

Schematic diagram of the coupled model simulation algorithm.

Figure 4.

The distribution of ox-LDL (a), macrophages (b) and foam cells (c) within the plaque area in early, baseline and advanced models. The red circle indicates the lumen area.

Figure 5.

Changes of intraplaque macrophage, ox-LDL and foam cell contents over time in early (a), baseline (b) and advanced (c) models.

Figure 6.

The proportion of macrophages polarized to M1 or M2 within the plaque in the early (a), baseline (b) and advanced (c) models.

Figure 7.

Changes of M1/M2 ratio in the three different models.

Figure 8.

(a) Changes in M1 concentration in early, baseline and advanced stage models after using Rb1-targeted macrophage therapy. (b) Changes in M2 concentration in the three models after using Rb1-targeted macrophage therapy. (c) Rate of change in lipoprotein area in the three models after using Rb1-targeted macrophage therapy. (d,e) Cell staining results of in vitro sections of mouse plaques before and after treatment with Rb1 [36].

Figure 9.

Changes of M1/M2 ratio after targeted therapy in early, baseline and advanced models.

Figure 10.

Effect of Rb1-targeted macrophages, addition of RCT cholesterol reversal transport effect, HDL-raising therapy, and combined HDL and Rb1 treatment on intraplaque foam cell concentration at early, baseline and late stages.