Abstract
Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on the context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute a continuous spectrum of phenotypes, of which the two extremes are denoted as classical (M1) and alternative (M2) activation. To quantitatively decode the underlying principles governing macrophage phenotypic polarization and thereby harness its therapeutic potential in human diseases, a systems-level approach is needed given the multitude of signaling pathways and intracellular regulation involved. Here we develop the first mechanism-based, multi-pathway computational model that describes the integrated signal transduction and macrophage programming under M1 (IFN-γ), M2 (IL-4) and cell stress (hypoxia) stimulation. Our model was calibrated extensively against experimental data, and we mechanistically elucidated several signature feedbacks behind the M1-M2 antagonism and investigated the dynamical shaping of macrophage phenotypes within the M1-M2 spectrum. Model sensitivity analysis also revealed key molecular nodes and interactions as targets with potential therapeutic values for the pathophysiology of peripheral arterial disease and cancer. Through simulations that dynamically capture the signal integration and phenotypic marker expression in the differential macrophage polarization responses, our model provides an important computational basis toward a more quantitative and network-centric understanding of the complex physiology and versatile functions of macrophages in human diseases.
Highlights
Macrophages are a class of innate immune cells that play essential roles in the progression and resolution of inflammatory responses, which are key to a variety of major human diseases [1]
The basic framework of our computational model (Figs 1 and S1) provides a physiology-based and literature data-driven description of macrophage polarization, which can be divided into three subparts: (i) IFN-γ-driven pathway, (ii) IL-4-driven pathway, and (iii) hypoxia-driven pathway
STAT6 upregulates the cellular expression of PPARγ which is a signature of oxidative metabolism and transcriptional regulation associated with M2-like macrophages [37, 38], and STAT6 can counteract the IFNγ-induced upregulation of IRF-1 by directly suppressing STAT1 transcriptional activities [39]
Summary
Macrophages are a class of innate immune cells that play essential roles in the progression and resolution of inflammatory responses, which are key to a variety of major human diseases [1]. A wealth of studies has investigated the differential phenotypes and corresponding regulatory functions of macrophages in disease settings including in major human diseases such as cancer, infectious and inflammatory disease, cardiovascular disease, and metabolic disease; evidence from in vitro and in vivo experiments confirmed the highly plastic nature of monocytes-macrophages, which suggest that cells of this lineage can be flexibly programmed by disease-driven environmental cues to exhibit a wide spectrum of activation and functional states [1,2,3,4,5]. M1 (or M1-like) phenotypes are often induced by pro-inflammatory cytokines such as IFN-γ (interferon gamma), TNF-α (tumor necrosis factor alpha) and IL-1β (interleukin 1 beta) as well as certain pathogen- and damage-associated molecular patterns (PAMP, DAMP) such as LPS (lipopolysaccharides) from gram-negative bacteria and HMGB1 (high mobility group box 1) which is a
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