title: Model-Based Characterization of Inflammatory Gene Expression Patterns of Activated Macrophages.
abstract: Macrophages are cells with remarkable plasticity. They integrate signals from their microenvironment leading to context-dependent polarization into classically (M1) or alternatively (M2) activated macrophages, representing two extremes of a broad spectrum of divergent phenotypes. Thereby, macrophages deliver protective and pro-regenerative signals towards injured tissue but, depending on the eliciting damage, may also be responsible for the generation and aggravation of tissue injury. Although incompletely understood, there is emerging evidence that macrophage polarization is critical for these antagonistic roles. To identify activation-specific expression patterns of chemokines and cytokines that may confer these distinct effects a systems biology approach was applied. A comprehensive literature-based Boolean model was developed to describe the M1 (LPS-activated) and M2 (IL-4/13-activated) polarization types. The model was validated using high-throughput transcript expression data from murine bone marrow derived macrophages. By dynamic modeling of gene expression, the chronology of pathway activation and autocrine signaling was estimated. Our results provide a deepened understanding of the physiological balance leading to M1/M2 activation, indicating the relevance of co-regulatory signals at the level of Akt1 or Akt2 that may be important for directing macrophage polarization.
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Julia
authors.identifier: 0000-0002-8189-9243
authors.initials: J
authors.lastname: Rex
authors.affiliation: Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Albrecht
authors.affiliation: Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehlting
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sawodny
authors.affiliation: Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-9871-0216
authors.initials: M
authors.lastname: Ederer
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Ronny
authors.identifier: 0000-0002-5653-7670
authors.initials: R
authors.lastname: Feuer
authors.affiliation: Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D016207:Cytokines / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D015203:Reproducibility of Results
chemical_list: D016207:Cytokines