Revisiting the inflammatory pathway with network biology

Abstract Motivation Inflammation is part of the complex function that addresses harmful stimuli, and the first phase of wound healing (WH), which guarantees living systems’ homeostasis. Deviances from physiology make inflammation turn acute (sepsis, 11M death/y) or chronic (non-communicable diseases, 41M death/y). Therefore, tackling inflammation is a key priority. We recently proposed (Maturo et al., 2020) to revise the conventional inflammatory pathway (innate immune response) to include WH (expanded inflammatory pathway). Methods We manually identified the Reactome pathways that include all reactions and species relevant to WH. Cytoscape was then used to perform the union of the SBML converted pathways, with the largest connected component being retained (732 nodes, 13.944 edges). The same was done for the innate immune response (R-HSA-168249.8) with 487 nodes, 11.744 edges. We then focused on: NF-kB (fundamental hub in all inflammatory reactions), TNF-α (renown target of inflammatory diseases) and RAC1 (key player in mechanotransduction events of WH). Results Preliminary topological results highlight the stability of closeness centrality, i.e. all molecules preserve their efficiency in spreading information. Conversely, betweenness centrality is stable for NF-kB (0.068), confirming NF-kB relevance, while halving its (very low) value in the expanded pathway for TNF-α (from 2.85E-06 to 1.29E-06). This indicates that the ability to bridge different parts of the graphs is less effective if we consider inflammation as an expanded concept, possibly contributing to explain the many side effects of anti-TNF-α therapies. Interestingly, RAC1 presents stable betweenness (from 0.094 to 0.093), comparable to NF-kB, supporting the hypothesis that WH-leveraging therapies could act on a relevant and stable target, so far neglected (Nardini et al., 2016). References Maturo, M.G., Soligo, M., Gibson, G., Manni, L., Nardini, C., 2020. The greater inflammatory pathway-high clinical potential by innovative predictive, preventive, and personalized medical approach. EPMA J 11, 1–16. https://doi.org/10.1007/s13167-019-00195-w Nardini, C., Devescovi, V., Liu, Y., Zhou, X., Lu, Y., Dent, J.E., 2016. Systemic Wound Healing Associated with local sub-Cutaneous Mechanical Stimulation. Sci. Rep. 6. https://doi.org/10.1038/srep3904