The AIR contains detailed information on pathways involved in acute inflammation and its resolution. The information has been collected from either manual extraction of molecular pathways involved in inflammatory processes or from public databases on clinical applications. All interactions from both approaches are referenced by recent publications and have been manually curated.

The complete AIR dataset consists of three major parts (as shown in the figure above):

1. Manually curated and annotated molecular pathways created in CellDesigner for defined biological processes involved in acute inflammation, named Submaps (bottom-up approach)
2. Molecular interaction maps (MIMs) constructed around seed molecules involved in clinical inflammatory settings from various databases, e.g. DisGeNET, HPRD, and IntAct (top-down approach)
3. Regulatory layers of micro RNA (miRNA), long non-coding RNA (lncRNA) and transcription factor (TF) interactions to elements in the AIR

However, in order to maintain an organized and clean view, the submaps are the only part visible to the user when accessing the AIR web platform. The other interactions are stored externally and can be accessed by analysis tools (i.e. plugins) to extend the informational content.

More information on the data generation and selection can be obtained from the manuscript.

 

Data content of the AIR (cumulative):

	Submaps	+ MIM	+regulatory layers
Nodes	1211	1867	7226
Interactions	1352	5358	22548

Network Topology

Most analyses require information on the network topology, i.e. paths between specific elements and their regulations. However, normally, network topology measures are computed on simple networks with bi- or unidirectional interactions between two elements. Complex biological reactions like the association of complexes and modifications (e.g. catalyzes) make the assessment of that information difficult. Therefore, we first transform the molecular interactions stored in the AIR into simple interaction requiring definitions on how to handle specific cases.

The resulting data of those conversions and topological measurements are static and can, therefore, be stored externally and updated regularly to fit the content of the AIR. Some analyses (see Plugins), can access this pre-analyzed information, and save computation time.

The AIR is a collection of molecular, subcellular, cellular, tissue and functional maps in the context of acute inflammation and inflammation resolution. Depending on the user’s need, the AIR provides various entry points to access all the curated information. The AIR is designed with the aim to serve diverse communities including clinicians, research scientists and drug developers from the pharmaceutical industry. Clinicians generally rely on the higher-level organization, i.e. at the cellular and tissue level to understand the pathophysiology of diseases. They are interested either in classifying patients into various risk groups or in therapy scheduling based on patient’s pathological reports. Time-series transcriptomics profiling of patients is getting popular day-by-day in hospitals, which motivate clinicians to use the data in therapy personalization without involving themselves in a data analysis pipeline 36. On the other hand, investigators are interested in generating new hypotheses for the design of experiments related to the phenotype under observation.

 

Submaps

Submaps provide a detailed overview of molecules, pathways and cell types involved in the regulation of biological processes (represented as phenotypes, as explained below) involved in inflammation and its resolution.

Phase	Submap title
Initiation	Pathogen associated molecular pattern (PAMPs) signaling
	Vasodilation vasoconstriction and permeability
	Leukocyte adhesion and transmigration
	Neutrophil chemotaxis
	Natural killer cell chemotaxis
	Biosynthesis of prostaglandins, thromboxanes and leukotrienes from arachidonic acid
	Biosynthesis of prostaglandins from EPA
Transition	Neutrophil apoptosis
	Macrophage phagocytosis
	Monocyte transmigration
	Efferocytosis
Resolution	Macrophage M1 to M2 class switch
	Biosynthesis of lipoxins from arachidonic acid
	Biosynthesis of resolvins, maresins, protectins and their conjugates from DHA
	Biosynthesis of E-class resolvins and lipoxins from EPA
	Resolvins mediated signaling cascade
	Protectins mediated signaling cascade
	Maresins mediated signaling cascade
	Lipoxins mediated signaling cascade
	STOP signaling
Homeostasis and return to tissue function	Wound healing

 

Elements

Most elements in the AIR are displayed as Systems Biology Graphical Notation (SBGN) symbols provided in CellDesigner 4.4:

Phenotypes represent more detailed and defined sub-processes on a biological or cellular scale that together describe the broad, inflammation-associated process of the whole submap. Example:

Submap	Containing Phenotypes
Vasoconstriction, vasodilation and permeability	regulation of vascular permeability membrane hyperpolarization vasodilation vasoconstriction tissue homeostasis platelet activation platelet aggregation platelet degranulation

 

Submaps contain multiple phenotypes and some phenotypes can occur in multiple submaps, e.g. the phenotype “apoptotic process” is involved in the submaps “Neutrophil apoptosis”, “Efferocytosis”, “Protectins signaling” and “Resolvins signaling”.

Complexes in the AIR can have two different meanings. Either they display a direct physical interaction and association of multiple molecules into a new functional unit (e.g. the CASP3:APAF complex in the figure below), or they describe a collection of functional and structural related molecules that perform the same reactions (e.g. IAPs).

 

Latter is displayed in the AIR as the standard “Complex” SBGN element modified by a dotted border and the “Family” tag. The type of complex influence how this element will be handled when analyzing network topology and mapping -omics data:

Examples of how different reactions are transformed into simple source-target relationships. A) Element families, as collections of functionally equal elements, are split into new reactions for every sub-element. B) Modifications of reactions are transformed into new, separate interactions between the modifier and the original target.

 

Entry Image

The entry image provides an overview of the biological processes and cell types involved in the above-described phases of inflammation and its resolution:

The basemap, i.e. the first map when entering the AIR, presents the entry image as a background with a selection of submaps that are integrated directly on the respective position over the image.:

When zooming into the submap areas, their associated pathway becomes visible and can be explored:

Overview

Clicking on „show overview“ will show the entry image with the submap areas as clickable red boxes:

Clicking on each of those boxes will directly open either the associated submap or another connecting overview image in a new window.