The inflammatory skin disease map (ISD map): an interactive computational resource focused on psoriasis and atopic dermatitis molecular mechanisms

Abstract

BackgroundInflammatory skin diseases (ISD), including atopic dermatitis (AD) and psoriasis (PsO), emerge from a complex network of inter- and intracellular biochemical interactions under the influence of genetic and environmental factors. The complexity of ISD mechanisms hinders translation of research findings into effective treatments and may explain the low remission rates despite the availability of modern targeted therapies. ObjectiveTo model AD- and PsO-associated mechanisms as networks of context-specific molecular interactions, the so-called ISD map, and to check the usefulness of this map as a graphically guided review of AD and PsO mechanisms and as a mechanistic hypothesis-generating platform. MethodsThe ISD map was built by assembling mechanistically resolved causal interactions obtained from relevant biomedical literature via manual curation. ResultsWe demonstrate that the ISD map (https://imi-biomap.elixir-luxembourg.org/) serves as an interactive, graphical review of AD and PsO molecular mechanisms and as a mechanistic hypothesis-generating platform. By analysing the map structure itself or the map integrated with genetics and functional genomics data, we could generate the following mechanistic hypotheses: (i) AD poor response to dupilumab is associated with a potential upregulation of IFNG, IL22, TSLP, IL-17A and IL25 signalling pathways in keratinocytes and/or single nucleotide polymorphisms (SNPs) in genes encoding regulators of IFNG expression in Th1 cells and (ii) PsO resistance to cytokine-induced apoptosis is associated with SNPs in IFNG signalling genes regulating SOCS1 in keratinocytes. Finally, the IL4/IL13 pathway in the AD submap of the ISD map was converted into a probabilistic Boolean model to simulate the effects of IFNG in sensory perception of itching after treatment with dupilumab. Our findings suggest that inhibiting both IFNG and IL4R may improve the therapeutic management of itching. ConclusionThe ISD map provides a significant interactive, computationally accessible resource of molecular knowledge on AD and PsO that can be used to graphically review known AD and PsO mechanisms and generate mechanistic hypotheses.