Construction of a large scale integrated map of macrophage pathogen recognition and effector systems

Abstract

BackgroundIn an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.ResultsThe diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.ConclusionsThe pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.

A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages

“…5B) detected a strong enrichment of an IFNb-stimulated gene (ISG) set in wild-type macro- phages. In particular, of the 251 genes in cluster #6, 132 (52.5%) were ISGs (based on either their inducibility by type I IFNs or the requirement of the type I IFN receptor for their activation in response to LPS) (Raza et al 2010;Cheng et al 2011). Seventy-eight of these 132 ISGs were down-regulated also in untreated cells (Fig.…”

Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps

“…While most models end at gene expression as the outputs, models incorporating gene and protein expression, cell physiology, cell-cell interactions, and cell-matrix interactions are lacking. Logic-based diagrams of signaling pathways can be used to frame cell responses at different activation stages with flexibility to allow orchestration across inputs [80]. …”

Knowledge gaps to understanding cardiac macrophage polarization following myocardial infarction

“…More complete knowledge maps and models that incorporate detailed signaling networks are needed to identify molecular drivers of macrophage polarization [44]. Building these models will require a framework that integrates both existing knowledge from the literature and new comprehensive molecular profiling with pathway analysis (Figure 2) [42–49]. Indeed, related approaches have been used to reconstruct networks and identify molecular drivers of cardiac myocyte hypertrophy and cardiac myofibroblast differentiation [50, 51].…”

“…Potential key drivers have been identified as isolated individual factors by us and others, yet their roles in stimulating macrophage function are still not completely understood (Table 2) [49, 53–61]. For example, IL-10 is a predominant anti-inflammatory cytokine elevated at days 5–7 post-MI.…”