A mechanistic integrative computational model of macrophage polarization: Implications in human pathophysiology

Chen Zhao, Adam C. Mirando, Richard J. Sové, Thalyta X. Medeiros, Brian H. Annex, Aleksander S. Popel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1007468
JournalPLoS Computational Biology
Volume15
Issue number11
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Pathophysiology
Macrophage
Macrophages
pathophysiology
Computational Model
macrophages
Polarization
polarization
phenotype
Phenotype
human diseases
antagonism
Activation
hypoxia
Chemical activation
physiology
Antagonism
sensitivity analysis
Cell Hypoxia
Hypoxia

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

A mechanistic integrative computational model of macrophage polarization : Implications in human pathophysiology. / Zhao, Chen; Mirando, Adam C.; Sové, Richard J.; Medeiros, Thalyta X.; Annex, Brian H.; Popel, Aleksander S.

In: PLoS Computational Biology, Vol. 15, No. 11, e1007468, 01.01.2019.

Research output: Contribution to journalArticle

Zhao, Chen ; Mirando, Adam C. ; Sové, Richard J. ; Medeiros, Thalyta X. ; Annex, Brian H. ; Popel, Aleksander S. / A mechanistic integrative computational model of macrophage polarization : Implications in human pathophysiology. In: PLoS Computational Biology. 2019 ; Vol. 15, No. 11.
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