Abstract
Macrophages derived from monocyte precursors undergo specific polarization processes which are influenced by the local tissue environment: classically activated (M1) macrophages, with a pro-inflammatory activity and a role of effector cells in Th1 cellular immune responses, and alternatively activated (M2) macrophages, with anti-inflammatory functions and involved in immunosuppression and tissue repair. At least three different subsets of M2 macrophages, namely, M2a, M2b, and M2c, are characterized in the literature based on their eliciting signals. The activation and polarization of macrophages is achieved through many, often intertwined, signaling pathways. To describe the logical relationships among the genes involved in macrophage polarization, we used a computational modeling methodology, namely, logical (Boolean) modeling of gene regulation. We integrated experimental data and knowledge available in the literature to construct a logical network model for the gene regulation driving macrophage polarization to the M1, M2a, M2b, and M2c phenotypes. Using the software GINsim and BoolNet, we analyzed the network dynamics under different conditions and perturbations to understand how they affect cell polarization. Dynamic simulations of the network model, enacting the most relevant biological conditions, showed coherence with the observed behavior of in vivo macrophages. The model could correctly reproduce the polarization toward the four main phenotypes as well as to several hybrid phenotypes, which are known to be experimentally associated to physiological and pathological conditions. We surmise that shifts among different phenotypes in the model mimic the hypothetical continuum of macrophage polarization, with M1 and M2 being the extremes of an uninterrupted sequence of states. Furthermore, model simulations suggest that anti-inflammatory macrophages are resilient to shift back to the pro-inflammatory phenotype.
Highlights
Macrophages and neutrophils of the innate immune system represent the first line of defense against most common microorganisms
We found that our model has five sets of steady states fitting the following five specific macrophage phenotypes markers according to literature (Figure 3): 3. M2a: all of PPARγ, signal transducer and activator of transcription 6 (STAT6), JMJD3 and IL-10 are active; 4
In the presence of IL-4, we noticed rapid expression of M2a master regulators (i.e., STAT6, PPARγ, and JMJD3) and the production of IL-10, with a slow decrease in the production of IL-12, indicating that M2a-related stimuli can immediately suppress the pro-inflammatory function of macrophage, as already evidenced in literature (Sica and Mantovani, 2012)
Summary
Macrophages and neutrophils of the innate immune system represent the first line of defense against most common microorganisms. Macrophages respond to extracellular stimuli upon contact with different cell types via endocytic, phagocytic, and secretory functions (Figure 1). Their activity is modulated by contact synapsis established with proximal cellular and molecular entities, including microorganisms, chemical mediators, and other macrophages (Gordon et al, 2014). Various stimuli, such as immune complexes (IC) together with LPS or interleukin-1 beta (IL-1β), glucocorticoids, transforming growth factor-β (TGF-β), and interleukin-10 (IL10), give rise to M2-like functional phenotypes that share properties with IL-4- or IL-13-activated macrophages [such as high expression of mannose receptor (MR) and IL-10, as well as TNFα, IL-1β, and IL-6] (Mantovani et al, 2004). Variations of the gene expression patterns corresponding to M1 or M2 are found in vivo (e.g., in the placenta and embryo, and during helminthic infection, Listeria infection, obesity, and cancer) (Raes et al, 2005; Biswas et al, 2006; Kraakman et al, 2014)
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