Objectives: Macrophages are cells with remarkable plasticity. They are able to integrate signals
from their microenvironment leading to context dependent differentiation into classically
activated macrophages (M1) or alternatively activated macrophages (M2). Within the
liver, macrophages are known to mediate important hepatoprotective and pro-regenerative
effects but may also be responsible for impaired hepatocyte function and liver injury
in response to microbial pathogens. The mechanisms responsible for this controversial
role of liver macrophages are still incompletely understood.
Methods and Results: Within the Virtual Liver Network (VLN), we applied a systems biology approach for
the identification of the differentiation specific, macrophage derived key mediator
pattern that may cause these distinct effects. Therefore, a comprehensive literature-based
Boolean model was developed in order to describe the activation of macrophages into
the M1 phenotype following stimulation with LPS (lipopolysaccharide) and into the
M2 phenotype in response to stimulation with the interleukins IL-4 and IL-13. This
logical model is validated and refined using high-throughput transcript expression
data from bone marrow derived macrophages (BMDM) and suggests that the PI3K and the
NFκB pathway may play a critical role as a switch regulating differentiation into
the M1 or M2 direction.
Conclusion: A Boolean model of the regulatory pathways controlling macrophage differentiation
into the M1 or the M2 direction has been established and validated to identify critical
intersections points that act as a molecular switch between M1 and M2 differentiation.
First simulations suggest that the NFκB and the PI3K pathway may play a role as a
molecular switch. This observation may be important for an in depth understanding
of processes that drive the hepatic acute phase response or liver regeneration.
Corresponding author: Albrecht, Ute
E-Mail:
Ute.Albrecht@hhu.de
