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.
Highlights
A large part of macrophage populations originate from monocytes released from the bone marrow that upon injury or inflammation migrate into several tissues of the body such as lung, liver, spleen, lymph node, bone or the central nervous system [1, 2]
Macrophages are essential cells of the immune system and indispensable for a defense against bacterial infection. They reside as resting, immune modulatory cells in several tissues of the human body where they continuously sense inputs from their local environment. They react to stimuli such as toxins, injury or bacterial products in a process termed macrophage activation or polarization
For a first description of macrophage activation, we constructed a comprehensive large-scale Boolean model including relevant signaling pathways activated in macrophages upon induction of M1 polarization by stimulation with LPS or induction of a M2 phenotype in response to combined stimulation with IL-4 and IL-13 (S1 Fig)
Summary
A large part of macrophage populations originate from monocytes released from the bone marrow that upon injury or inflammation migrate into several tissues of the body such as lung, liver, spleen, lymph node, bone or the central nervous system [1, 2] As it harbors the body’s largest pool of sessile tissue macrophages the liver owns a distinguished role within the macrophage system. Lineage tracing experiments [3, 4] suggest that under homeostatic conditions macrophages recruited from circulating monocytes are of minor importance for maintenance of the population of tissue resident liver macrophages ( termed as Kupffer cells) These cells have janitorial and immune regulatory functions but play a subordinate role for induction and regulation of inflammatory reactions evoked by tissue injury. They play a critical role for the generation and control of inflammatory reactions that either cause and aggravate tissue injury or mediate processes required for tissue repair [3], which are the basis for the unique capability of the liver to regenerate [5]
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