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Front. Physiol. | doi: 10.3389/fphys.2018.01659

Gene regulatory network modeling of macrophage differentiation corroborates the continuum hypothesis of polarization states

  • 1Università degli Studi di Roma Tor Vergata, Italy
  • 2American University of Sharjah, United Arab Emirates
  • 3Istituto per le Applicazioni del Calcolo, Consiglio Nazionale Delle Ricerche (CNR), Italy
  • 4La Sapienza University of Rome, Italy

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 analysed 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 behaviour 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.

Keywords: macrophage, differentiation, phenotype, Model, Gene regulating network, polarization, Immune System

Received: 31 Jul 2018; Accepted: 02 Nov 2018.

Edited by:

Matteo Barberis, University of Amsterdam, Netherlands

Reviewed by:

Nathan Weinstein, Instituto de Ecología, Universidad Autónoma de Mexico, Mexico
Carlos Villarreal, National Autonomous University of Mexico, Mexico  

Copyright: © 2018 Palma, Jarrah, Tieri, Cesareni and Castiglione. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Filippo Castiglione, Consiglio Nazionale Delle Ricerche (CNR), Istituto per le Applicazioni del Calcolo, Rome, 00185, Italy,